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Pathak T, Benson JC, Tang PW, Trebak M, Hempel N. Crosstalk between calcium and reactive oxygen species signaling in cancer revisited. Cell Calcium 2025; 127:103014. [PMID: 40139005 DOI: 10.1016/j.ceca.2025.103014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
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Affiliation(s)
- Trayambak Pathak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - J Cory Benson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Priscilla W Tang
- UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mohamed Trebak
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Nadine Hempel
- Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Malignant Hematology & Medical Oncology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
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Zeng J, Tong S, Liu J, Liu S, Mungur R, Chen S. MiR-433 inhibits cell invasion of glioblastoma via direct targeting TRPM8 based on bioinformatic analysis and experimental validation. Gene 2025; 936:149121. [PMID: 39581355 DOI: 10.1016/j.gene.2024.149121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 11/13/2024] [Accepted: 11/21/2024] [Indexed: 11/26/2024]
Abstract
Understanding the essential role of miRNA in regulating cell invasion in glioblastoma opens up new avenues for targeted therapeutic interventions in the future. By screening out eligible miRNA expression data sets from the GEO database, the WGCNA package based on the R language is further used to construct a co-expression network model of the chip data set, to identify modules related to disease states and perform pivotal miRNA screening on the related modules. The target relationship between miRNA and TRPM8 was verified by bioinformatics and luciferase gene report, and the effect of miRNA overexpression on TRPM8 protein level was analyzed by Western blot. The result of miR-433 overexpression on the invasion ability of glioblastoma cells in vitro was examined by scratch test and Transwell invasion test. The results of this study indicate that the selected target miR-433 has a strong binding relationship with TRPM8 and can effectively regulate its expression. Furthermore, overexpression of miR-433 was found to inhibit the invasion ability of glioblastoma cells by targeting TRPM8. These data demonstrate that miR-433 can target TRPM8 to inhibit glioblastoma cell invasion.
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Affiliation(s)
- Jianping Zeng
- Department of Neurosurgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University. Nanchang 330006, Jiangxi Province, PR China.
| | - Shoufang Tong
- Department of Transfusion Medicine, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang Provincial People's Hospital) Hangzhou Medical College, Taizhou, Zhejiang, PR China
| | - Jing Liu
- Department of Pharmacy, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University. Nanchang 330006, Jiangxi Province, PR China
| | - Shuai Liu
- Department of Neurosurgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University. Nanchang 330006, Jiangxi Province, PR China
| | - Rajneesh Mungur
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang University, Hangzhou 310000, Zhejiang Province, PR China
| | - Shangshi Chen
- Department of Neurosurgery, The 1st Affiliated Hospital, Jiangxi Medical College, Nanchang University. Nanchang 330006, Jiangxi Province, PR China.
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Becker J, Ellerkmann CS, Schmelzer H, Hermann C, Lützel K, Gudermann T, Konrad DB, Trauner D, Storch U, Mederos Y Schnitzler M. Optical Control of TRPM8 Channels with Photoswitchable Menthol. Angew Chem Int Ed Engl 2025; 64:e202416549. [PMID: 39660776 DOI: 10.1002/anie.202416549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/21/2024] [Accepted: 12/10/2024] [Indexed: 12/12/2024]
Abstract
Transient receptor potential melastatin 8 (TRPM8) channels are well known as sensors for cold temperatures and cooling agents such as menthol and icilin and these channels are tightly regulated by the membrane lipid phosphoinositol-4,5-bisphosphate (PIP2). Since TRPM8 channels emerged as promising drug targets for treating pain, itching, obesity, cancer, dry eye disease, and inflammation, we aimed at developing a high-precision TRPM8 channel activator, to achieve spatiotemporal control of TRPM8 activity with light. In this study, we designed, synthesized and characterized the first photoswitchable TRPM8 activator azo-menthol (AzoM). AzoM enables optical control of endogenously and heterologously expressed TRPM8 channels with UV and blue light which is demonstrated by performing patch-clamp experiments. Moreover, AzoM facilitates the reliable determination of activation, inactivation, and deactivation kinetics thereby providing further insights into the channel gating. Using AzoM, the specific roles of individual amino acids for AzoM or PIP2 binding and for sensitization by PIP2 can be elucidated. Altogether, AzoM represents as a high-precision pharmaceutical tool for reversible control of TRPM8 channel function that enhances our biophysical understanding of TRPM8 channels and holds the potential to support the development of novel pharmaceuticals.
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Affiliation(s)
- Jasmin Becker
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany
| | - Clara S Ellerkmann
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany
| | - Hannah Schmelzer
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany
| | - Christian Hermann
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany
| | - Kyra Lützel
- Department of Pharmacy, Ludwig Maximilian University of Munich, Butenandtstr. 5-13, 81377, Munich, Germany
| | - Thomas Gudermann
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany
- Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, 81377, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, 80336, Munich, Germany
| | - David B Konrad
- Department of Pharmacy, Ludwig Maximilian University of Munich, Butenandtstr. 5-13, 81377, Munich, Germany
| | - Dirk Trauner
- Department of Chemistry College of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania, 19104-6323, United States
| | - Ursula Storch
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany
- Institute of Pharmacy, University of Regensburg, Universitätsstr. 31, 93040, Regensburg, Germany
| | - Michael Mederos Y Schnitzler
- Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Goethestr. 33, 80336, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, 80336, Munich, Germany
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Chen Z, Xie H, Liu J, Zhao J, Huang R, Xiang Y, Wu H, Tian D, Bian E, Xiong Z. Roles of TRPM channels in glioma. Cancer Biol Ther 2024; 25:2338955. [PMID: 38680092 PMCID: PMC11062369 DOI: 10.1080/15384047.2024.2338955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 04/01/2024] [Indexed: 05/01/2024] Open
Abstract
Gliomas are the most common type of primary brain tumor. Despite advances in treatment, it remains one of the most aggressive and deadly tumor of the central nervous system (CNS). Gliomas are characterized by high malignancy, heterogeneity, invasiveness, and high resistance to radiotherapy and chemotherapy. It is urgent to find potential new molecular targets for glioma. The TRPM channels consist of TRPM1-TPRM8 and play a role in many cellular functions, including proliferation, migration, invasion, angiogenesis, etc. More and more studies have shown that TRPM channels can be used as new therapeutic targets for glioma. In this review, we first introduce the structure, activation patterns, and physiological functions of TRPM channels. Additionally, the pathological mechanism of glioma mediated by TRPM2, 3, 7, and 8 and the related signaling pathways are described. Finally, we discuss the therapeutic potential of targeting TRPM for glioma.
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Affiliation(s)
- Zhigang Chen
- Department of Neurosurgery, The Translational Research Institute for Neurological Disorders, The First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu, P. R. China
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Han Xie
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Jun Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - JiaJia Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Ruixiang Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Yufei Xiang
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Haoyuan Wu
- Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China
| | - Dasheng Tian
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Erbao Bian
- Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhang Xiong
- Department of Neurosurgery, The Translational Research Institute for Neurological Disorders, The First Affiliated Hospital (Yijishan Hospital), Wannan Medical College, Wuhu, P. R. China
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Soni D, Khan H, Chauhan S, Kaur A, Dhankhar S, Garg N, Singh TG. Exploring therapeutic potential: Targeting TRPM7 in neurodegenerative diseases. Int Immunopharmacol 2024; 142:113142. [PMID: 39298812 DOI: 10.1016/j.intimp.2024.113142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/06/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024]
Abstract
The ions Ca2+ and Mg2+, which are both present in the body, have been demonstrated to be crucial in the control of a variety of neuronal processes. Transient melastatin-7 (TRPM7) channel plays an important role in controlling Ca2+ and Mg2+ homeostasis, which is crucial for biological processes. The review will also examine how changes in TRPM7 function or expression can lead to neurodegeneration.Even though eight different TRPM channels have been found so far, the channel properties, activation mechanisms, and physiological responses exhibited by these channels can vary greatly from one another. Only TRPM6 and TRPM7 out of the eight TRPM channels were found to have a high permeability to both Ca2+ and Mg2+. In contrast to TRPM6 channels, which are not highly expressed in neuronal cells, TRPM7 channels are widely distributed throughout the nervous system, so they will be the sole focus of this article. It is possible that, in the future, for the treatment of neurodegenerative disorder new therapeutic drug targets will be developed as a direct result of research into the specific roles played by TRPM7 channels in several different neurodegenerative conditions as well as the factors that are responsible for TRPM7 channel regulation.
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Affiliation(s)
- Diksha Soni
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
| | - Samrat Chauhan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
| | - Amarjot Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
| | - Sanchit Dhankhar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
| | - Nitika Garg
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India.
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Zhang N, Zhang H, Li S, Wu W, Luo P, Liu Z, Chen Y, Xia Z, Huang C, Cheng Q. Uncovering the predictive and immunomodulatory potential of transient receptor potential melastatin family-related CCNE1 in pan-cancer. Mol Cancer 2024; 23:258. [PMID: 39551726 PMCID: PMC11572178 DOI: 10.1186/s12943-024-02169-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 11/05/2024] [Indexed: 11/19/2024] Open
Abstract
Millions of new cases of cancer are diagnosed worldwide each year, making it a serious public health concern. Developments in customized therapy and early detection have significantly enhanced treatment for and results from cancer. Therefore, it is important to investigate new molecular biomarkers. In this study, we created an efficient transient receptor potential melastatin (TRPM) family members-related TRPM-Score for 17 solid tumors. CCNE1, produced from TRPM-Score, was found to be an exceptional biomarker through several sophisticated machine learning and deep learning computational techniques. TRPM-Score and CCNE1 immunotherapeutic prediction, immunological characteristics, and predictive value were thoroughly assessed. In most cancer types, CCNE1 was a substantially dangerous marker. Additional in vitro tests validated CCNE1's immunomodulatory properties, demonstrating that silencing impeded macrophage movement and decreased PD-L1 expression. Additionally, CCNE1 may accurately predict responses to cancer immunotherapy. These findings indicate that the TRPM family-particularly CCNE1, which is associated with TRPM-is a significant player in the pan-cancer domain and can be utilized as a therapeutic target and prognostic biomarkers, especially in immuno-oncology. The thorough characterization of the TRPM family and the discovery of CCNE1 as a crucial downstream effector mark important developments in our comprehension of pan-cancer biology.
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Affiliation(s)
- Nan Zhang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shuyu Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wantao Wu
- Department of Thyroid and Breast Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Chen
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhiwei Xia
- Department of Neurology, Hunan Aerospace Hospital, Hunan Normal University, Changsha, China.
| | - Chenshen Huang
- Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
- Xiangya Hospital, National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China.
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Chinigò G, Ruffinatti FA, Munaron L. The potential of TRP channels as new prognostic and therapeutic targets against prostate cancer progression. Biochim Biophys Acta Rev Cancer 2024; 1879:189226. [PMID: 39586480 DOI: 10.1016/j.bbcan.2024.189226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 10/28/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
Prostate cancer (PCa) is the second deadliest cancer among men worldwide. Particularly critical is its development towards metastatic androgen-independent forms for which the current therapies are ineffective. Indeed, the 5-year relative survival for PCa drops dramatically to 34 % in the presence of metastases. The superfamily of Transient Receptor Potential (TRP) channels could answer the urgent request to identify new prognostic and therapeutic tools against metastatic PCa. Indeed, this class of ion channels revealed an appealing de-regulation during PCa development and its progression towards aggressive forms. Altered expression and/or functionality of several TRPs have been associated with the PCa metastatic cascade by significantly impacting tumor growth, invasiveness, and angiogenesis. In this review, we will dissect the contribution of TRP channels in such hallmarks of PCa and then discuss their applicability as new prognostic and therapeutic agents in the fight against metastatic PCa. In particular, the great potential of TRPM8, TRPV6, and TRPA1 in opening the way to new treatment perspectives will be highlighted.
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Affiliation(s)
- Giorgia Chinigò
- University of Turin, Department of Life Sciences and Systems Biology, via Accademia Albertina 13, 10123 Turin, Italy.
| | | | - Luca Munaron
- University of Turin, Department of Life Sciences and Systems Biology, via Accademia Albertina 13, 10123 Turin, Italy.
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Chen Z, Vallega KA, Boda VK, Quan Z, Wang D, Fan S, Wang Q, Ramalingam SS, Li W, Sun S. Targeting Transient Receptor Potential Melastatin-2 (TRPM2) Enhances Therapeutic Efficacy of Third Generation EGFR Inhibitors against EGFR Mutant Lung Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2310126. [PMID: 39044361 PMCID: PMC11425210 DOI: 10.1002/advs.202310126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 06/30/2024] [Indexed: 07/25/2024]
Abstract
There is an urgent need to fully understand the biology of third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, and to develop mechanism-driven strategies to manage their acquired resistance. Transient receptor potential melastatin-2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR-TKIs and acquired resistance to EGFR-TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR-TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy-optimized TRPM2 inhibitors.
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Affiliation(s)
- Zhen Chen
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Karin A. Vallega
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Vijay K. Boda
- Department of Pharmaceutical SciencesCollege of PharmacyUniversity of Tennessee Health Science CenterMemphisTN38163USA
| | - Zihan Quan
- Department of PathologyThe Second Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Dongsheng Wang
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Songqing Fan
- Department of PathologyThe Second Xiangya HospitalCentral South UniversityChangshaHunan410011P. R. China
| | - Qiming Wang
- Department of Internal MedicineThe Affiliated Cancer Hospital of Zhengzhou UniversityHenan Cancer HospitalZhengzhou450008P. R. China
| | - Suresh S. Ramalingam
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
| | - Wei Li
- Department of Pharmaceutical SciencesCollege of PharmacyUniversity of Tennessee Health Science CenterMemphisTN38163USA
| | - Shi‐Yong Sun
- Department of Hematology and Medical OncologyEmory University School of Medicine and Winship Cancer InstituteAtlantaGA30047USA
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Liu Y, Yao X, Zhao W, Xu J, Zhang H, Huang T, Wu C, Yang J, Tang C, Ye Q, Hu W, Wang Q. A comprehensive analysis of TRP-related gene signature, and immune infiltration in patients with colorectal cancer. Discov Oncol 2024; 15:357. [PMID: 39154317 PMCID: PMC11330954 DOI: 10.1007/s12672-024-01227-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024] Open
Abstract
BACKGROUND Transient receptor potential (TRP) channels are involved in the development and progression of tumors. However, their role in colorectal cancer (CRC) remains unclear, and this study aims to investigate the role of TRP-related genes in CRC. METHODS Data was obtained from The Cancer Genome Atlas (TCGA) database, and analyses were conducted on the GSE14333 and GSE38832 datasets to assess the prognosis and mark TRP-related genes (TRGs). Subsequently, clustering analysis and immune infiltration analysis were performed to explore the relevant TRGs. In vitro validation of key TRGs' gene and protein expression was conducted using human colon cancer cells. RESULTS Compared to normal tissues, 8 TRGs were significantly upregulated in CRC, while 11 were downregulated. TRPA1 was identified as a protective prognostic factor, whereas TRPM5 (HR = 1.349), TRPV4 (HR = 1.289), and TRPV3 (HR = 1.442) were identified as prognostic risk factors. Receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analyses yielded similar results. Additionally, lower expression of TRPA1 and higher expression of TRPV4 and TRPM5 were negatively correlated with patient prognosis, and experimental validation confirmed the underexpression of TRPA1 and overexpression of TRPV4 and TRPM5 in CRC cell lines. CONCLUSION This study identifies a TRP channel-related prognosis in CRC, providing a novel approach to stratifying CRC prognosis.
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Affiliation(s)
- Yicheng Liu
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Xiaobing Yao
- Gastrointestinal surgery, Yueyang hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenjun Zhao
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Jin Xu
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Haiyan Zhang
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Ting Huang
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Chuang Wu
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Jiajia Yang
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Cheng Tang
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Qianqian Ye
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weiye Hu
- Department of Liver, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qingming Wang
- Department of Anorectal Surgery, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China.
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Huang L, Lin R, Chen J, Qi Y, Lin L. Magnesium Ion: A New Switch in Tumor Treatment. Biomedicines 2024; 12:1717. [PMID: 39200180 PMCID: PMC11351748 DOI: 10.3390/biomedicines12081717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/12/2024] [Accepted: 07/26/2024] [Indexed: 09/02/2024] Open
Abstract
The magnesium ion is an essential cation in the human body and participates in numerous physiological activities. A deficiency in magnesium ions is closely associated with tumor development, and supplementation with magnesium ions has been shown to partially inhibit tumor growth. However, the specific mechanisms by which magnesium ions suppress tumor proliferation remain unclear. Currently, studies have revealed that mitochondria may serve as a crucial intermediate link in the regulation of tumors by magnesium ions. Mitochondria might intervene in the proliferation and invasion of tumor cells by modulating energy metabolism and oxidative stress levels. Regrettably, there has been no comprehensive review of the role of magnesium in cancer therapy to date. Therefore, this article provides a comprehensive scrutiny of the relationship between magnesium ions and tumors, aiming to offer insights for clinical tumor treatment strategies involving magnesium ion intervention.
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Affiliation(s)
- Leyi Huang
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China;
- Department of Biochemistry and Molecular Biology, Fujian Medical University, Fuzhou 350122, China; (R.L.)
| | - Renxi Lin
- Department of Biochemistry and Molecular Biology, Fujian Medical University, Fuzhou 350122, China; (R.L.)
- Experimental Teaching Center of Basic Medicine, Fujian Medical University, Fuzhou 350122, China
| | - Jiaxi Chen
- Department of Biochemistry and Molecular Biology, Fujian Medical University, Fuzhou 350122, China; (R.L.)
| | - Yuanlin Qi
- Department of Biochemistry and Molecular Biology, Fujian Medical University, Fuzhou 350122, China; (R.L.)
| | - Ling Lin
- Department of Biochemistry and Molecular Biology, Fujian Medical University, Fuzhou 350122, China; (R.L.)
- Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Medical University, Fuzhou 350122, China
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Thiel G, Rössler OG. Signal Transduction of Transient Receptor Potential TRPM8 Channels: Role of PIP5K, Gq-Proteins, and c-Jun. Molecules 2024; 29:2602. [PMID: 38893478 PMCID: PMC11174004 DOI: 10.3390/molecules29112602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/24/2024] [Accepted: 05/26/2024] [Indexed: 06/21/2024] Open
Abstract
Transient receptor potential melastatin-8 (TRPM8) is a cation channel that is activated by cold and "cooling agents" such as menthol and icilin, which induce a cold sensation. The stimulation of TRPM8 activates an intracellular signaling cascade that ultimately leads to a change in the gene expression pattern of the cells. Here, we investigate the TRPM8-induced signaling pathway that links TRPM8 channel activation to gene transcription. Using a pharmacological approach, we show that the inhibition of phosphatidylinositol 4-phosphate 5 kinase α (PIP5K), an enzyme essential for the biosynthesis of phosphatidylinositol 4,5-bisphosphate, attenuates TRPM8-induced gene transcription. Analyzing the link between TRPM8 and Gq proteins, we show that the pharmacological inhibition of the βγ subunits impairs TRPM8 signaling. In addition, genetic studies show that TRPM8 requires an activated Gα subunit for signaling. In the nucleus, the TRPM8-induced signaling cascade triggers the activation of the transcription factor AP-1, a complex consisting of a dimer of basic region leucine zipper (bZIP) transcription factors. Here, we identify the bZIP protein c-Jun as an essential component of AP-1 within the TRPM8-induced signaling cascade. In summary, with PIP5K, Gq subunits, and c-Jun, we identified key molecules in TRPM8-induced signaling from the plasma membrane to the nucleus.
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Affiliation(s)
- Gerald Thiel
- Department of Medical Biochemistry and Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany;
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12
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Hirata Y, Mishima E. Membrane Dynamics and Cation Handling in Ferroptosis. Physiology (Bethesda) 2024; 39:73-87. [PMID: 38193763 PMCID: PMC11283900 DOI: 10.1152/physiol.00029.2023] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/10/2024] Open
Abstract
Ferroptosis, a regulated cell death hallmarked by excessive lipid peroxidation, is implicated in various (patho)physiological contexts. During ferroptosis, lipid peroxidation leads to a diverse change in membrane properties and the dysregulation of ion homeostasis via the cation channels, ultimately resulting in plasma membrane rupture. This review illuminates cellular membrane dynamics and cation handling in ferroptosis regulation.
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Affiliation(s)
- Yusuke Hirata
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Eikan Mishima
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany
- Division of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan
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13
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Köles L, Ribiczey P, Szebeni A, Kádár K, Zelles T, Zsembery Á. The Role of TRPM7 in Oncogenesis. Int J Mol Sci 2024; 25:719. [PMID: 38255793 PMCID: PMC10815510 DOI: 10.3390/ijms25020719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/30/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
This review summarizes the current understanding of the role of transient receptor potential melastatin-subfamily member 7 (TRPM7) channels in the pathophysiology of neoplastic diseases. The TRPM family represents the largest and most diverse group in the TRP superfamily. Its subtypes are expressed in virtually all human organs playing a central role in (patho)physiological events. The TRPM7 protein (along with TRPM2 and TRPM6) is unique in that it has kinase activity in addition to the channel function. Numerous studies demonstrate the role of TRPM7 chanzyme in tumorigenesis and in other tumor hallmarks such as proliferation, migration, invasion and metastasis. Here we provide an up-to-date overview about the possible role of TRMP7 in a broad range of malignancies such as tumors of the nervous system, head and neck cancers, malignant neoplasms of the upper gastrointestinal tract, colorectal carcinoma, lung cancer, neoplasms of the urinary system, breast cancer, malignant tumors of the female reproductive organs, prostate cancer and other neoplastic pathologies. Experimental data show that the increased expression and/or function of TRPM7 are observed in most malignant tumor types. Thus, TRPM7 chanzyme may be a promising target in tumor therapy.
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Affiliation(s)
- László Köles
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
| | - Polett Ribiczey
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
| | - Andrea Szebeni
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
| | - Kristóf Kádár
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
| | - Tibor Zelles
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
- Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, H-1083, Budapest, Hungary
| | - Ákos Zsembery
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
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14
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Li F, Chen X. Contribution and underlying mechanisms of lncRNA TRPM2-AS in the development and progression of human cancers. Pathol Res Pract 2023; 251:154887. [PMID: 37871443 DOI: 10.1016/j.prp.2023.154887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/07/2023] [Accepted: 10/11/2023] [Indexed: 10/25/2023]
Abstract
Long-stranded non-coding RNAs (lncRNAs) are RNA molecules that are longer than 200 nucleotides and do not code for proteins. They play a significant role in various biological processes, including epigenetics, cell cycle, and cell differentiation. Many studies have shown that the occurrence of human cancer is closely related to the abnormal expression of lncRNA. In recent years, lncRNAs have been a hot topic in cancer research. TRPM2-AS, a novel lncRNA, is aberrantly expressed in many human cancers, and its overexpression is strongly linked to poor clinical outcomes in patients. It has been demonstrated that TRPM2-AS acts as a ceRNA, participates in signaling pathways, and interacts with biological proteins and other molecular mechanisms to regulate gene expression. In addition, it can regulate the proliferation, migration, invasion, apoptosis, and treatment resistance of cancer cells. As a result, TRPM2-AS may be a potential target for cancer treatment and a possible biomarker for cancer prognosis. This review outlined the expression, biological processes, and molecular mechanisms of TRPM2-AS in various malignancies, and discussed potential therapeutic uses.
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Affiliation(s)
- Fei Li
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Xiuwei Chen
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, China.
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15
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Wang ZB, Zhang X, Xiao F, Liu ZQ, Liao QJ, Wu N, Wang J. Roles of TRPM7 in ovarian cancer. Biochem Pharmacol 2023; 217:115857. [PMID: 37839677 DOI: 10.1016/j.bcp.2023.115857] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/17/2023]
Abstract
Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.
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Affiliation(s)
- Zhi-Bin Wang
- Hunan Gynecological Tumor Clinical Research Center; Hunan Key Laboratory of Cancer Metabolism; Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410008, PR China
| | - Xiu Zhang
- Hunan Gynecological Tumor Clinical Research Center; Hunan Key Laboratory of Cancer Metabolism; Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410008, PR China
| | - Fen Xiao
- Hunan Gynecological Tumor Clinical Research Center; Hunan Key Laboratory of Cancer Metabolism; Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410008, PR China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha 410078, PR China
| | - Qian-Jin Liao
- Hunan Gynecological Tumor Clinical Research Center; Hunan Key Laboratory of Cancer Metabolism; Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410008, PR China
| | - Nayiyuan Wu
- Hunan Gynecological Tumor Clinical Research Center; Hunan Key Laboratory of Cancer Metabolism; Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410008, PR China.
| | - Jing Wang
- Hunan Gynecological Tumor Clinical Research Center; Hunan Key Laboratory of Cancer Metabolism; Hunan Cancer Hospital, and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410008, PR China.
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16
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Palchevskyi S, Czarnocki-Cieciura M, Vistoli G, Gervasoni S, Nowak E, Beccari AR, Nowotny M, Talarico C. Structure of human TRPM8 channel. Commun Biol 2023; 6:1065. [PMID: 37857704 PMCID: PMC10587237 DOI: 10.1038/s42003-023-05425-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 10/05/2023] [Indexed: 10/21/2023] Open
Abstract
TRPM8 is a non-selective cation channel permeable to both monovalent and divalent cations that is activated by multiple factors, such as temperature, voltage, pressure, and changes in osmolality. It is a therapeutic target for anticancer drug development, and its modulators can be utilized for several pathological conditions. Here, we present a cryo-electron microscopy structure of a human TRPM8 channel in the closed state that was solved at 2.7 Å resolution. Our structure comprises the most complete model of the N-terminal pre-melastatin homology region. We also visualized several lipids that are bound by the protein and modeled how the human channel interacts with icilin. Analyses of pore helices in available TRPM structures showed that all these structures can be grouped into different closed, desensitized and open state conformations based on the register of the pore helix S6 which positions particular amino acid residues at the channel constriction.
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Affiliation(s)
- Sergii Palchevskyi
- Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, 02-109, Warsaw, Poland
- Cell Signalling Department, Institute of Molecular Biology and Genetics NASU, 03143, Kyiv, Ukraine
| | - Mariusz Czarnocki-Cieciura
- Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, 02-109, Warsaw, Poland
| | - Giulio Vistoli
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25, I-20133, Milano, Italy
| | - Silvia Gervasoni
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25, I-20133, Milano, Italy
- Department of Physics, University of Cagliari, I-09042, Monserrato, Italy
| | - Elżbieta Nowak
- Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, 02-109, Warsaw, Poland
| | - Andrea R Beccari
- Dompé Farmaceutici SpA, EXSCALATE, Via Tommaso De Amicis, 95, I-80131, Napoli, Italy
| | - Marcin Nowotny
- Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, 02-109, Warsaw, Poland.
| | - Carmine Talarico
- Dompé Farmaceutici SpA, EXSCALATE, Via Tommaso De Amicis, 95, I-80131, Napoli, Italy.
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17
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Okada Y, Numata T, Sabirov RZ, Kashio M, Merzlyak PG, Sato-Numata K. Cell death induction and protection by activation of ubiquitously expressed anion/cation channels. Part 3: the roles and properties of TRPM2 and TRPM7. Front Cell Dev Biol 2023; 11:1246955. [PMID: 37842082 PMCID: PMC10576435 DOI: 10.3389/fcell.2023.1246955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/15/2023] [Indexed: 10/17/2023] Open
Abstract
Cell volume regulation (CVR) is a prerequisite for animal cells to survive and fulfill their functions. CVR dysfunction is essentially involved in the induction of cell death. In fact, sustained normotonic cell swelling and shrinkage are associated with necrosis and apoptosis, and thus called the necrotic volume increase (NVI) and the apoptotic volume decrease (AVD), respectively. Since a number of ubiquitously expressed ion channels are involved in the CVR processes, these volume-regulatory ion channels are also implicated in the NVI and AVD events. In Part 1 and Part 2 of this series of review articles, we described the roles of swelling-activated anion channels called VSOR or VRAC and acid-activated anion channels called ASOR or PAC in CVR and cell death processes. Here, Part 3 focuses on therein roles of Ca2+-permeable non-selective TRPM2 and TRPM7 cation channels activated by stress. First, we summarize their phenotypic properties and molecular structure. Second, we describe their roles in CVR. Since cell death induction is tightly coupled to dysfunction of CVR, third, we focus on their participation in the induction of or protection against cell death under oxidative, acidotoxic, excitotoxic, and ischemic conditions. In this regard, we pay attention to the sensitivity of TRPM2 and TRPM7 to a variety of stress as well as to their capability to physicall and functionally interact with other volume-related channels and membrane enzymes. Also, we summarize a large number of reports hitherto published in which TRPM2 and TRPM7 channels are shown to be involved in cell death associated with a variety of diseases or disorders, in some cases as double-edged swords. Lastly, we attempt to describe how TRPM2 and TRPM7 are organized in the ionic mechanisms leading to cell death induction and protection.
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Affiliation(s)
- Yasunobu Okada
- National Institute for Physiological Sciences (NIPS), Okazaki, Japan
- Department of Integrative Physiology, Graduate School of Medicine, AkitaUniversity, Akita, Japan
- Department of Physiology, School of Medicine, Aichi Medical Uniersity, Nagakute, Japan
- Department of Physiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan
| | - Tomohiro Numata
- Department of Integrative Physiology, Graduate School of Medicine, AkitaUniversity, Akita, Japan
| | - Ravshan Z. Sabirov
- Institute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent, Uzbekistan
| | - Makiko Kashio
- National Institute for Physiological Sciences (NIPS), Okazaki, Japan
- Department of Physiology, School of Medicine, Aichi Medical Uniersity, Nagakute, Japan
| | - Peter G. Merzlyak
- Institute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent, Uzbekistan
| | - Kaori Sato-Numata
- Department of Integrative Physiology, Graduate School of Medicine, AkitaUniversity, Akita, Japan
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18
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Huang W, Wu Y, Luo N, Shuai X, Guo J, Wang C, Yang F, Liu L, Liu S, Cheng Z. Identification of TRPM2 as a prognostic factor correlated with immune infiltration in ovarian cancer. J Ovarian Res 2023; 16:169. [PMID: 37608401 PMCID: PMC10463424 DOI: 10.1186/s13048-023-01225-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 06/24/2023] [Indexed: 08/24/2023] Open
Abstract
INTRODUCTION Ovarian cancer (OC) is one of the most common gynecologic malignant cancers with the current survival rate remaining low. TRPM2 has been reported as a survival predictor in various cancers but not in OC. The aim of this study is to explore the role and its underlying mechanism of TRPM2 in OC. METHODS The transcriptome data and clinical data were obtained from TCGA, GTEx, and GEO (GSE17260). DriverDBv3 and PrognoScan were used to analyze survival correlations. GSEA analysis was performed to uncover the underlying mechanism. The correlations between TRPM2 and immune score, immune cell infiltration were analyzed by TIMER2.0. RESULTS TRPM2 was highly expressed in OC and high TRPM2 expression was related to the poor prognosis based on the Kaplan-Meier curves, univariate and multivariate analysis. The enrichment analysis suggested that TRPM2 was involved in immune-related pathways. Positive correlations were also observed between TRPM2 expression and immune score and immune cells covering B cells, T cells, macrophage, neutrophil, and myeloid dendritic cells. We also found that TRPM2 was positively related to immune checkpoints including ICOSLG, CD40, CD86, etc. TRPM2 expression had a positive correlation with M2 macrophage, but not with M1 macrophage. Besides, TRPM2 showed a strong positive correlation with pyroptosis-related genes including NLRP3, NLRC4, NOD2, NOD1, IL1B, GSDMD. CONCLUSION Our study demonstrated that TRPM2 is a poor prognostic prediction factor in ovarian cancer and is correlated to the immune microenvironment and pyroptosis. TRPM2 may act as a new immunotherapy target, which promoted the survival rate of OC patients.
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Affiliation(s)
- Wei Huang
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China
| | - Yuliang Wu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China
| | - Ning Luo
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China
| | - Xueqian Shuai
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China
| | - Jing Guo
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China
| | - Chunyan Wang
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
| | - Fanchun Yang
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China
| | - Li Liu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China
| | - Shupeng Liu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China.
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China.
| | - Zhongping Cheng
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China.
- Gynecologic Minimally Invasive Surgery Research Center, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China.
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19
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Foster HM, Carle MN, Jira LR, Koh DW. TRPM2 Channels: A Potential Therapeutic Target in Melanoma? Int J Mol Sci 2023; 24:10437. [PMID: 37445615 DOI: 10.3390/ijms241310437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/09/2023] [Accepted: 06/15/2023] [Indexed: 07/15/2023] Open
Abstract
The transient receptor potential, the melastatin (TRPM) subfamily, which consists of eight known members, appears to have significant importance in melanoma progression, treatment, and prognosis. As several members were originally cloned from cancerous tissue, initial studies aimed towards identifying TRPM involvement in cancer progression and tumorigenesis. For relevance in skin cancer, previous research has shown roles for several TRPM members in skin cancer progression, growth, and patient prognosis. One unique member, TRPM2, appears to have notable therapeutic potential in the treatment of melanoma. Previous and recent studies have demonstrated increased TRPM2 expression levels in melanoma, as well as important roles for TRPM2 in melanoma growth, proliferation, and survival. TRPM2 is thus an emerging target in the treatment of melanoma, where TRPM2 antagonism may offer an additional treatment option for melanoma patients in the future.
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Affiliation(s)
- Hattie M Foster
- Department of Pharmaceutical & Biomedical Sciences, Ohio Northern University, Ada, OH 45810, USA
| | - McKenzie N Carle
- Department of Pharmaceutical & Biomedical Sciences, Ohio Northern University, Ada, OH 45810, USA
| | - Lukas R Jira
- Department of Pharmaceutical & Biomedical Sciences, Ohio Northern University, Ada, OH 45810, USA
| | - David W Koh
- Department of Pharmaceutical & Biomedical Sciences, Ohio Northern University, Ada, OH 45810, USA
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20
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Ali ES, Chakrabarty B, Ramproshad S, Mondal B, Kundu N, Sarkar C, Sharifi-Rad J, Calina D, Cho WC. TRPM2-mediated Ca 2+ signaling as a potential therapeutic target in cancer treatment: an updated review of its role in survival and proliferation of cancer cells. Cell Commun Signal 2023; 21:145. [PMID: 37337283 PMCID: PMC10278317 DOI: 10.1186/s12964-023-01149-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 04/28/2023] [Indexed: 06/21/2023] Open
Abstract
The transient receptor potential melastatin subfamily member 2 (TRPM2), a thermo and reactive oxygen species (ROS) sensitive Ca2+-permeable cation channel has a vital role in surviving the cell as well as defending the adaptability of various cell groups during and after oxidative stress. It shows higher expression in several cancers involving breast, pancreatic, prostate, melanoma, leukemia, and neuroblastoma, indicating it raises the survivability of cancerous cells. In various cancers including gastric cancers, and neuroblastoma, TRPM2 is known to conserve viability, and several underlying mechanisms of action have been proposed. Transcription factors are thought to activate TRPM2 channels, which is essential for cell proliferation and survival. In normal physiological conditions with an optimal expression of TRPM2, mitochondrial ROS is produced in optimal amounts while regulation of antioxidant expression is carried on. Depletion of TRPM2 overexpression or activity has been shown to improve ischemia-reperfusion injury in organ levels, reduce tumor growth and/or viability of various malignant cancers like breast, gastric, pancreatic, prostate, head and neck cancers, melanoma, neuroblastoma, T-cell and acute myelogenous leukemia. This updated and comprehensive review also analyzes the mechanisms by which TRPM2-mediated Ca2+ signaling can regulate the growth and survival of different types of cancer cells. Based on the discussion of the available data, it can be concluded that TRPM2 may be a unique therapeutic target in the treatment of several types of cancer. Video Abstract.
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Affiliation(s)
- Eunus S. Ali
- College of Medicine and Public Health, Flinders University, Bedford Park, 5042 Australia
- Gaco Pharmaceuticals, Dhaka, 1000 Bangladesh
- Present Address: Department of Biochemistry and Molecular Genetics, and Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, 303 E Superior St, Chicago, IL 60611 USA
| | | | - Sarker Ramproshad
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400 Bangladesh
| | - Banani Mondal
- Department of Pharmacy, Ranada Prasad Shaha University, Narayanganj, 1400 Bangladesh
| | - Neloy Kundu
- Pharmacy Discipline, Khulna University, Khulna, 9208 Bangladesh
| | - Chandan Sarkar
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100 Bangladesh
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, 200349 Romania
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, China
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21
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Nadezhdin KD, Correia L, Narangoda C, Patel DS, Neuberger A, Gudermann T, Kurnikova MG, Chubanov V, Sobolevsky AI. Structural mechanisms of TRPM7 activation and inhibition. Nat Commun 2023; 14:2639. [PMID: 37156763 PMCID: PMC10167348 DOI: 10.1038/s41467-023-38362-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/27/2023] [Indexed: 05/10/2023] Open
Abstract
The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. TRPM7 is implicated in neuronal and cardiovascular disorders, tumor progression and has emerged as a new drug target. Here we use cryo-EM, functional analysis, and molecular dynamics simulations to uncover two distinct structural mechanisms of TRPM7 activation by a gain-of-function mutation and by the agonist naltriben, which show different conformational dynamics and domain involvement. We identify a binding site for highly potent and selective inhibitors and show that they act by stabilizing the TRPM7 closed state. The discovered structural mechanisms provide foundations for understanding the molecular basis of TRPM7 channelopathies and drug development.
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Affiliation(s)
- Kirill D Nadezhdin
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
| | - Leonor Correia
- Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany
| | - Chamali Narangoda
- Chemistry Department, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Dhilon S Patel
- Chemistry Department, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Arthur Neuberger
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
| | - Thomas Gudermann
- Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany
- Comprehensive Pneumology Center, German Center for Lung Research (DZL), Munich, Germany
| | - Maria G Kurnikova
- Chemistry Department, Carnegie Mellon University, Pittsburgh, PA, USA.
| | - Vladimir Chubanov
- Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany.
| | - Alexander I Sobolevsky
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
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22
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Zhang XM, Song Y, Zhu XY, Wang WJ, Fan XL, El-Aziz TMA. MITOCHONDRIA: The dual function of the transient receptor potential melastatin 2 channels from cytomembrane to mitochondria. Int J Biochem Cell Biol 2023; 157:106374. [PMID: 36708986 DOI: 10.1016/j.biocel.2023.106374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 12/20/2022] [Accepted: 01/24/2023] [Indexed: 01/26/2023]
Abstract
Mitochondria are closely related to oxidative stress and play an important role in maintaining cell functional homeostasis and meeting cell energy demand. The transient receptor potential melastatin 2 (TRPM2) channel affects the occurrence and progression of diseases by regulating mitochondrial function. TRPM2 channel promotes Ca2+ influx to affect 18 kDa translocator protein (TSPO), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), adenosine triphosphate (ATP) production, and mitochondrial autophagy. The mechanism of Ca2+ influx into the mitochondria by TRPM2 is abundant. Interestingly, the TRPM2 channel inhibits the production of mitochondrial ROS in cancer cells and promotes the production of mitochondrial ROS in normal cells, which induces cell death in normal cells but proliferation in cancer cells. TRPM2 can be a potential target for the treatment of various diseases due to its role as a molecular link between mitochondria and Ca2+ signals.
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Affiliation(s)
- Xiao-Min Zhang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
| | - Xin-Yi Zhu
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Wen-Jun Wang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Xu-Li Fan
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Tarek Mohamed Abd El-Aziz
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA; Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
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23
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Ciaglia T, Vestuto V, Bertamino A, González-Muñiz R, Gómez-Monterrey I. On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications. Front Oncol 2023; 12:1065935. [PMID: 36844925 PMCID: PMC9948629 DOI: 10.3389/fonc.2022.1065935] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/15/2022] [Indexed: 02/11/2023] Open
Abstract
The transient melastatin receptor potential (TRPM) ion channel subfamily functions as cellular sensors and transducers of critical biological signal pathways by regulating ion homeostasis. Some members of TRPM have been cloned from cancerous tissues, and their abnormal expressions in various solid malignancies have been correlated with cancer cell growth, survival, or death. Recent evidence also highlights the mechanisms underlying the role of TRPMs in tumor epithelial-mesenchymal transition (EMT), autophagy, and cancer metabolic reprogramming. These implications support TRPM channels as potential molecular targets and their modulation as an innovative therapeutic approach against cancer. Here, we discuss the general characteristics of the different TRPMs, focusing on current knowledge about the connection between TRPM channels and critical features of cancer. We also cover TRPM modulators used as pharmaceutical tools in biological trials and an indication of the only clinical trial with a TRPM modulator about cancer. To conclude, the authors describe the prospects for TRPM channels in oncology.
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Affiliation(s)
- Tania Ciaglia
- Dipartimento di Farmacia (DIFARMA), Università degli Studi di Salerno, Fisciano, Italy
| | - Vincenzo Vestuto
- Dipartimento di Farmacia (DIFARMA), Università degli Studi di Salerno, Fisciano, Italy
| | - Alessia Bertamino
- Dipartimento di Farmacia (DIFARMA), Università degli Studi di Salerno, Fisciano, Italy
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24
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Progress in the Structural Basis of thermoTRP Channel Polymodal Gating. Int J Mol Sci 2023; 24:ijms24010743. [PMID: 36614186 PMCID: PMC9821180 DOI: 10.3390/ijms24010743] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
The thermosensory transient receptor potential (thermoTRP) family of ion channels is constituted by several nonselective cation channels that are activated by physical and chemical stimuli functioning as paradigmatic polymodal receptors. Gating of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity. Given that thermoTRP channels integrate diverse physical and chemical stimuli, a thorough understanding of the molecular mechanisms underlying polymodal gating has been pursued, including the interplay between stimuli and differences between family members. Despite its complexity, recent advances in cryo-electron microscopy techniques are facilitating this endeavor by providing high-resolution structures of these channels in different conformational states induced by ligand binding or temperature that, along with structure-function and molecular dynamics, are starting to shed light on the underlying allosteric gating mechanisms. Because dysfunctional thermoTRP channels play a pivotal role in human diseases such as chronic pain, unveiling the intricacies of allosteric channel gating should facilitate the development of novel drug-based resolving therapies for these disorders.
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25
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Ochoa SV, Casas Z, Albarracín SL, Sutachan JJ, Torres YP. Therapeutic potential of TRPM8 channels in cancer treatment. Front Pharmacol 2023; 14:1098448. [PMID: 37033630 PMCID: PMC10073478 DOI: 10.3389/fphar.2023.1098448] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/20/2023] [Indexed: 04/11/2023] Open
Abstract
Cancer is a multifactorial process associated with changes in signaling pathways leading to cell cycle variations and gene expression. The transient receptor potential melastatin 8 (TRPM8) channel is a non-selective cation channel expressed in neuronal and non-neuronal tissues, where it is involved in several processes, including thermosensation, differentiation, and migration. Cancer is a multifactorial process associated with changes in signaling pathways leading to variations in cell cycle and gene expression. Interestingly, it has been shown that TRPM8 channels also participate in physiological processes related to cancer, such as proliferation, survival, and invasion. For instance, TRPM8 channels have an important role in the diagnosis, prognosis, and treatment of prostate cancer. In addition, it has been reported that TRPM8 channels are involved in the progress of pancreatic, breast, bladder, colon, gastric, and skin cancers, glioblastoma, and neuroblastoma. In this review, we summarize the current knowledge on the role of TRPM8 channels in cancer progression. We also discuss the therapeutic potential of TRPM8 in carcinogenesis, which has been proposed as a molecular target for cancer therapy.
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Affiliation(s)
- Sara V. Ochoa
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá, Colombia
- Semillero de Investigación, Biofísica y Fisiología de Canales Iónicos, Pontificia Universidad Javeriana, Bogotá, Colombia
- *Correspondence: Sara V. Ochoa, ; Yolima P. Torres,
| | - Zulma Casas
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Sonia L. Albarracín
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Jhon Jairo Sutachan
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Yolima P. Torres
- Departamento de Nutrición y Bioquímica, Pontificia Universidad Javeriana, Bogotá, Colombia
- *Correspondence: Sara V. Ochoa, ; Yolima P. Torres,
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26
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Zhang Z, Kang L, Yan X, Leng Z, Fang K, Chen T, Xu M. Global Trends and Hotspots of Transient Receptor Potential Melastatin 8 Research from 2002 to 2021: A Bibliometric Analysis. J Pain Res 2022; 15:3881-3892. [PMID: 36536695 PMCID: PMC9759117 DOI: 10.2147/jpr.s393582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/06/2022] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Transient receptor potential channels are the major temperature and nociceptive receptors in the human body and transient receptor potential melastatin 8 (TRPM8) is the cold-sensitive and non-selective cation channel. In our study, we performed a bibliometric analysis of TRPM8 from 2002 to 2021 to summarize the current research status and potential research direction in the future. METHODS The TRPM8-related publications were selected from the Web of Science Core Collection SCI-EXPANDED database from 2002 to 2021. The publication details, such as authors, titles, and author keywords, were used for bibliometric analysis and network visualization to present the current state of TRPM8 research. RESULTS A total of 1035 articles met the inclusion criteria. The number of TRPM8-related articles has grown rapidly over the past two decades. The USA has the largest number of publications, citations, and international collaborations. The TRPM8-related articles are mainly published and cited in neurological journals, such as the Journal of Neuroscience (41 publications and 2171 local citations). Prevarskaya N. has the most publications (26), and Patapoutian A. has been cited the most (1414 local citations). The popular disciplines in TRPM8 research include Neurosciences and Neurology, Pharmacology and Pharmacy, Biochemistry, and Molecular Biology. Research hotspots are mainly TRP channel, calcium, prostate cancer, proliferation, pain, cold, nociception, and inflammation. CONCLUSION Our bibliometric analysis demonstrates that the number of TRPM8 studies has increased from 2002 to 2021. The global research trends and hotspots include the activation mechanism of TRPM8 in neurons, the role of TRPM8 in neuronal and non-neuronal diseases, and therapeutic target research.
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Affiliation(s)
- Zehua Zhang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Le Kang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China
| | - Xiaohan Yan
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Zhuyun Leng
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Kang Fang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Tao Chen
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
| | - Meidong Xu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
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27
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Zong GF, Deng R, Yu SY, Wang AY, Wei ZH, Zhao Y, Lu Y. Thermo-Transient Receptor Potential Channels: Therapeutic Potential in Gastric Cancer. Int J Mol Sci 2022; 23:ijms232315289. [PMID: 36499622 PMCID: PMC9740781 DOI: 10.3390/ijms232315289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/08/2022] Open
Abstract
Over the last decade, researchers have found abnormal expression of transient receptor potential (TRP) channels. In particular, members of the thermally sensitive subclass (thermo-TRPs) are involved in many disease processes. Moreover, they have a vital role in the occurrence and development of gastric cancer (GC). Accordingly, thermo-TRPs constitute a major pharmacological target, and the elucidation of the mechanisms underlying their response to physiological stimuli or drugs is key for notable advances in GC treatment. Therefore, this paper summarizes the existing literature about thermo-TRP protein expression changes that are linked to the incidence and progression of GC. The review also discusses the implication of such association to pathology and cell physiology and identifies potential thermo-TRP protein targets for diagnosis and treatment of GC.
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Affiliation(s)
- Gang-Fan Zong
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Rui Deng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Su-Yun Yu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, No.138 Xianlin Avenue, Nanjing 210023, China
| | - Ai-Yun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhong-Hong Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yang Zhao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, No.138 Xianlin Avenue, Nanjing 210023, China
- Correspondence: (Y.Z.); (Y.L.); Tel.: +86-025-13382098417 (Y.Z.); +86-02515605190001 (Y.L.)
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Correspondence: (Y.Z.); (Y.L.); Tel.: +86-025-13382098417 (Y.Z.); +86-02515605190001 (Y.L.)
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28
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Liu H, Dilger JP, Lin J. A pan-cancer-bioinformatic-based literature review of TRPM7 in cancers. Pharmacol Ther 2022; 240:108302. [PMID: 36332746 DOI: 10.1016/j.pharmthera.2022.108302] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/20/2022] [Accepted: 10/25/2022] [Indexed: 11/16/2022]
Abstract
TRPM7, a divalent cation-selective channel with kinase domains, has been widely reported to potentially affect cancers. In this study, we conducted multiple bioinformatic analyses based on open databases and reviewed articles that provided evidence for the effects of TRPM7 on cancers. The purposes of this paper are 1) to provide a pan-cancer overview of TRPM7 in cancers; 2) to summarize evidence of TRPM7 effects on cancers; 3) to identify potential future studies of TRPM7 in cancer. Bioinformatics analysis revealed that no cancer-related TRPM7 mutation was found. TRPM7 is aberrantly expressed in most cancer types but the cancer-noncancer expression pattern varies across cancer types. TRPM7 was not associated with survival, TMB, or cancer stemness in most cancer types. TRPM7 affected drug sensitivity and tumor immunity in some cancer types. The in vitro evidence, preclinical in vivo evidence, and clinical evidence for TRPM7 effects on cancers as well as TRPM7 kinase substrate and TRPM7-targeting drugs associated with cancers were summarized to facilitate comparison. We matched the bioinformatics evidence to literature evidence, thereby unveiling potential avenues for future investigation of TRPM7 in cancers. We believe that this paper will help orient research toward important and relevant aspects of the role of TRPM7 in cancers.
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Affiliation(s)
- Hengrui Liu
- Department of Anesthesiology, Health Science Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - James P Dilger
- Department of Anesthesiology, Health Science Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jun Lin
- Department of Anesthesiology, Health Science Center, Stony Brook University, Stony Brook, NY 11794, USA.
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29
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Wang Y, Lu R, Chen P, Cui R, Ji M, Zhang X, Hou P, Qu Y. Promoter methylation of transient receptor potential melastatin-related 7 (TRPM7) predicts a better prognosis in patients with Luminal A breast cancers. BMC Cancer 2022; 22:951. [PMID: 36064388 PMCID: PMC9446581 DOI: 10.1186/s12885-022-10038-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
Breast cancer is the most common female tumors arising worldwide, and genetic and epigenetic events are constantly accumulated in breast tumorigenesis. The melastatin-related transient receptor potential 7 channel (TRPM7) is a nonselective cation channel, mainly maintaining Zn2+, Ca2+ and Mg2+ homeostasis. It is also involved in regulating proliferation and migration in various cancers including breast cancer. However, epigenetic alterations (such as promoter methylation) of TRPM7 and their correlation with clinical outcomes in breast cancer patients remain largely unclear. In this study, we found that TRPM7 was highly expressed in the luminal A subtype of breast cancers but no other subtypes compared with GTEx (Genotype-Tissue Expression Rad) or normal samples by analyzing the TCGA database. Correspondingly, TRPM7 was methylated in 42.7% (93 of 219) of breast cancers. Further studies found that promoter methylation of TRPM7 were significantly associated with better clinical outcomes in breast cancer patients, especially in the Luminal A subtype. Besides, methylated TRPM7 was correlated with less number of metastatic lymph nodes and longer local failure free survival time in this subtype. In summary, our data indicate that promoter methylation of TRPM7 may predict poor prognosis in patients with luminal A breast cancer.
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Affiliation(s)
- Yuanyuan Wang
- Department of Endocrinology, Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Rong Lu
- Department of Endocrinology, Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Pu Chen
- Department of Endocrinology, Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Rongrong Cui
- Department of Endocrinology, Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Meiju Ji
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Xiaozhi Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Peng Hou
- Department of Endocrinology, Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
| | - Yiping Qu
- Department of Endocrinology, Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
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30
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Zhang H, Zhang X, Wang X, Sun H, Hou C, Yu Y, Wang S, Yin F, Yang Z. Comprehensive Analysis of TRP Channel–Related Genes in Patients With Triple-Negative Breast Cancer for Guiding Prognostic Prediction. Front Oncol 2022; 12:941283. [PMID: 35875096 PMCID: PMC9300844 DOI: 10.3389/fonc.2022.941283] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 05/25/2022] [Indexed: 11/30/2022] Open
Abstract
Background Triple-negative breast cancer (TNBC) is a special subtype of breast cancer. Transient Receptor Potential (TRP) channel superfamily has emerged as a novel and interesting target in a variety of tumors. However, the association of TRP channel–related genes with TNBC is still unclear. Methods The The Cancer Genome Atlas (TCGA)-TNBC and GSE58812 datasets were downloaded from the public database. The differentially expressed TRP channel–related genes (DETGs) were screened by limma package, and mutations of the above genes were analyzed. Subsequently, new molecular subtypes in TNBC-based DETGs were explored by consensus clustering analysis. In addition, Lasso–Cox regression analysis was used to divide it into two robust risk subtypes: high-risk group and low-risk group. The accuracy and distinguishing ability of above models were verified by a variety of methods, including Kaplan–Meier survival analysis, ROC analysis, calibration curve, and PCA analysis. Meanwhile, CIBERSORT algorithm was used to excavate status of immune-infiltrating cells in TNBC tissues. Last, we explored the therapeutic effect of drugs and underlying mechanisms of risk subgroups by pRRophetic package and GSEA algorithm, respectively. Results A total of 19 DETGs were identified in 115 TNBC and 113 normal samples from TCGA database. In addition, missense mutation and SNP were the most common variant classification. According to Lasso–Cox regression analysis, the risky formula performed best when nine genes were used: TRPM5, TRPV2, HTR2B, HRH1, P2RY2, MAP2K6, NTRK1, ADCY6, and PRKACB. Subsequently, Kaplan–Meier survival analysis, ROC analysis, calibration curve, and Principal Components Analysis (PCA) analysis showed an excellent accuracy for predicting OS using risky formula in each cohort (P < 0.05). Specifically, high-risk group had a shorter OS compared with low-risk group. In addition, T-cell CD4 memory activated and macrophages M1 were enriched in normal tissues, whereas Tregs were increased in tumor tissues. Note that the low-risk group was better therapeutic effect to docetaxel, doxorubicin, cisplatin, paclitaxel, and gemcitabine than the high-risk group (P < 0.05). Last, in vitro assays, Quantitative Real-time PCR (qRT-PCR) indicated that TRPM5 was significantly highly expressed in MDA-MB-231 and MDA-MB-468 cells compared with that in MCF-10A cells (P < 0.01). Conclusion We identified a risky formula based on expression of TRP channel–related genes that can predict prognosis, therapeutic effect, and status of tumor microenvironment for patients with TNBC.
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Affiliation(s)
- Haojie Zhang
- The Second Medical College, Binzhou Medical University, Yantai, China
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Xiangsheng Zhang
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Xiaohong Wang
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
- *Correspondence: Xiaohong Wang, ; Zhenlin Yang,
| | - Hongguang Sun
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Changran Hou
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yue Yu
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Song Wang
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Fangxu Yin
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Zhenlin Yang
- Department of Thyroid and Breast Surgery, Binzhou Medical University Hospital, Binzhou, China
- *Correspondence: Xiaohong Wang, ; Zhenlin Yang,
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31
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Audero MM, Prevarskaya N, Fiorio Pla A. Ca 2+ Signalling and Hypoxia/Acidic Tumour Microenvironment Interplay in Tumour Progression. Int J Mol Sci 2022; 23:7377. [PMID: 35806388 PMCID: PMC9266881 DOI: 10.3390/ijms23137377] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/26/2022] [Accepted: 06/27/2022] [Indexed: 01/18/2023] Open
Abstract
Solid tumours are characterised by an altered microenvironment (TME) from the physicochemical point of view, displaying a highly hypoxic and acidic interstitial fluid. Hypoxia results from uncontrolled proliferation, aberrant vascularization and altered cancer cell metabolism. Tumour cellular apparatus adapts to hypoxia by altering its metabolism and behaviour, increasing its migratory and metastatic abilities by the acquisition of a mesenchymal phenotype and selection of aggressive tumour cell clones. Extracellular acidosis is considered a cancer hallmark, acting as a driver of cancer aggressiveness by promoting tumour metastasis and chemoresistance via the selection of more aggressive cell phenotypes, although the underlying mechanism is still not clear. In this context, Ca2+ channels represent good target candidates due to their ability to integrate signals from the TME. Ca2+ channels are pH and hypoxia sensors and alterations in Ca2+ homeostasis in cancer progression and vascularization have been extensively reported. In the present review, we present an up-to-date and critical view on Ca2+ permeable ion channels, with a major focus on TRPs, SOCs and PIEZO channels, which are modulated by tumour hypoxia and acidosis, as well as the consequent role of the altered Ca2+ signals on cancer progression hallmarks. We believe that a deeper comprehension of the Ca2+ signalling and acidic pH/hypoxia interplay will break new ground for the discovery of alternative and attractive therapeutic targets.
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Affiliation(s)
- Madelaine Magalì Audero
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
| | - Natalia Prevarskaya
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
| | - Alessandra Fiorio Pla
- U1003—PHYCEL—Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, Villeneuve d’Ascq, 59000 Lille, France; (M.M.A.); (N.P.)
- Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy
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32
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Boudaka A, Tominaga M. Physiological and Pathological Significance of Esophageal TRP Channels: Special Focus on TRPV4 in Esophageal Epithelial Cells. Int J Mol Sci 2022; 23:ijms23094550. [PMID: 35562940 PMCID: PMC9099744 DOI: 10.3390/ijms23094550] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/16/2022] [Accepted: 04/19/2022] [Indexed: 12/10/2022] Open
Abstract
Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel that is broadly expressed in different human tissues, including the digestive system, where it acts as a molecular sensor and a transducer that regulates a variety of functional activities. Despite the extensive research to determine the role of this channel in the physiology and pathophysiology of different organs, the unique morphological and functional features of TRPV4 in the esophagus remain largely unknown. Ten years ago, TRPV4 was shown to be highly expressed in esophageal epithelial cells where its activation induces Ca2+-dependent ATP release, which, in turn, mediates several functions, ranging from mechanosensation to wound healing. This review summarizes the research progress on TRPV4, and focuses on the functional expression of TRPV4 in esophageal epithelium and its possible role in different esophageal diseases that would support TRPV4 as a candidate target for future therapeutic approaches to treat patients with these conditions.
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Affiliation(s)
- Ammar Boudaka
- Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khoud, P.O. Box 35, Muscat 123, Oman
- Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki 444-8787, Aichi, Japan;
- Correspondence:
| | - Makoto Tominaga
- Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki 444-8787, Aichi, Japan;
- Department of Physiological Sciences, SOKENDAI (The Graduate University for Advanced Studies), Okazaki 444-8787, Aichi, Japan
- Exploratory Research Center on Life and Living Systems, Thermal Biology Group, Okazaki 444-8787, Aichi, Japan
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Fujino T. Transient Receptor Potential Melastatin 8, a sensor of cold temperatures mediates expression of cyclin-dependent kinase inhibitor, p21/Cip1, a regulator of epidermal cell proliferation. J Toxicol Sci 2022; 47:117-123. [PMID: 35236803 DOI: 10.2131/jts.47.117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Transient Receptor Potential Melastatin 8 (TRPM8) is a calcium-permeable, non-selective cation channel of the transient receptor potential superfamily, required for the transduction of moderate cold temperatures. TRPM8 is also known to regulate proliferation of prostate, pancreatic, breast, and melanoma carcinoma cells. Here, we examined a key factor in the regulation of TRPM8-mediated proliferation of epidermal cells, which are directly affected by cold temperatures. Experiments involving knockdown and ectopic expression of TRPM8 in normal keratinocyte HaCaT and squamous carcinoma SAS cells suggest that TRPM8 inhibits cell proliferation by upregulating the expression of cyclin-dependent inhibitor p21/Cip1. Whereas these findings were observed in the absence of an endogenous agonists, additions of the synthetic TRPM8 agonist icilin reduced DNA synthesis in HaCaT cells but stimulated that in SAS cells by altering p21/Cip1 levels in a TRPM8-independent manner, indicating that icilin poses a risk of stimulating carcinoma cell proliferation. Unexpectedly, the TRPM8 blocker, used for the treatment of overactive bladder and bladder pain, N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl] oxy}-N-(2-thienylmethyl) benzamide hydrochloride salt (AMTB) reduced DNA synthesis by upregulating p21/Cip1 expression. However, another TRPM8 blocker, N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin- 2-yl) tetrahydropyrazine-1 (2H)-carbox-amide (BCTC), stimulated DNA synthesis by downregulating p21/Cip1 expression, indicating that it may pose a risk of carcinogenesis associated with dysregulated cell cycles when used to treat overactive bladder and bladder pain.
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Affiliation(s)
- Tomofumi Fujino
- Department of Hygiene and Health Sciences, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
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Li X, Miao S, Li F, Ye F, Yue G, Lu R, Shen H, Ye Y. Cellular Calcium Signals in Cancer Chemoprevention and Chemotherapy by Phytochemicals. Nutr Cancer 2022; 74:2671-2685. [PMID: 35876249 DOI: 10.1080/01635581.2021.2020305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Xue Li
- Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, China
- Department of Laboratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Shuhan Miao
- Department of Health Care, Zhenjiang Fourth Peoples Hospital, Zhenjiang, China
| | - Feng Li
- Department of Thoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Fen Ye
- Department of Clinical Laboratory Center, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Guang Yue
- Department of Internal Medicine, The Third Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Rongzhu Lu
- Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, China
- Center for Experimental Research, Affiliated Kunshan Hospital, Jiangsu University, Kunshan, Suzhou, China
| | - Haijun Shen
- Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yang Ye
- Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, China
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Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel-Part 2: TRPM4 in Health and Disease. Pharmaceuticals (Basel) 2021; 15:ph15010040. [PMID: 35056097 PMCID: PMC8779181 DOI: 10.3390/ph15010040] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Transient receptor potential melastatin 4 (TRPM4) is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+ sensitive and permeable for monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions; it regulates membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the currently available knowledge about the physiological and pathophysiological roles of TRPM4 in various tissues. These include the physiological functions of TRPM4 in the cells of the Langerhans islets of the pancreas, in various immune functions, in the regulation of vascular tone, in respiratory and other neuronal activities, in chemosensation, and in renal and cardiac physiology. TRPM4 contributes to pathological conditions such as overactive bladder, endothelial dysfunction, various types of malignant diseases and central nervous system conditions including stroke and injuries as well as in cardiac conditions such as arrhythmias, hypertrophy, and ischemia-reperfusion injuries. TRPM4 claims more and more attention and is likely to be the topic of research in the future.
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Kim W, Park S, Kwon W, Kim D, Park JK, Han JE, Cho GJ, Han SH, Sung Y, Yi JK, Kim MO, Ryoo ZY, Choi SK. Suppression of transient receptor potential melastatin 7 regulates pluripotency, proliferation, and differentiation of mouse embryonic stem cells via mechanistic target of rapamycin-extracellular signal-regulated kinase activation. J Cell Biochem 2021; 123:547-567. [PMID: 34958137 DOI: 10.1002/jcb.30199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 11/26/2021] [Accepted: 12/13/2021] [Indexed: 11/06/2022]
Abstract
Mouse embryonic stem cells (mESCs) are a widely used model for their diverse availability in studying early embryonic development and their application in regenerative treatment of various intractable diseases. Transient receptor potential melastatin 7 (Trpm7) regulates Ca2+ as a nonselective ion channel and is essential for early embryonic development; however, the precise role of Trpm7 in mESCs has not been clearly elucidated. In this study, we showed that the inhibition of Trpm7 affects the pluripotency and self-renewal of mESCs. We found that short hairpin RNA (shRNA)-mediated suppression of Trpm7 resulted in decreased expression of transcriptional regulators, Oct4 and Sox2, which maintain stemness in mESCs. In addition, Trpm7 knockdown led to alterations in the basic properties of mESCs, such as decreased proliferation, cell cycle arrest at the G0/G1 phase, and increased apoptosis. Furthermore, embryoid body (EB) formation and teratoma formation assays revealed abnormal regulation of differentiation due to Trpm7 knockdown, including the smaller size of EBs, elevated ectodermal differentiation, and diminished endodermal and mesodermal differentiation. We found that EB Day 7 samples displayed decreased intracellular Ca2+ levels compared to those of the scrambled group. Finally, we identified that these alterations induced by Trpm7 knockdown occurred due to decreased phosphorylation of mechanistic target of rapamycin (mTOR) and subsequent activation of extracellular signal-regulated kinase (ERK) in mESCs. Our findings suggest that Trpm7 could be a novel regulator for maintaining stemness and modulating the differentiation of mESCs.
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Affiliation(s)
- Wansoo Kim
- Core Protein Resources Center, DGIST, Daegu, South Korea.,School of Life Science, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu, South Korea
| | - Song Park
- Core Protein Resources Center, DGIST, Daegu, South Korea.,Department of Brain and Cognitive Sciences, DGIST, Daegu, South Korea
| | - Wookbong Kwon
- Core Protein Resources Center, DGIST, Daegu, South Korea.,Division of Biotechnology, DGIST, Daegu, South Korea
| | - Daehwan Kim
- Core Protein Resources Center, DGIST, Daegu, South Korea.,School of Life Science, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu, South Korea
| | - Jin-Kyu Park
- College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea
| | - Jee Eun Han
- College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea
| | - Gil-Jae Cho
- College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea
| | - Se-Hyeon Han
- Department of News-team, SBS (Seoul Broadcasting System), Seoul, South Korea.,School of Media Communication, Hanyang University, Seoul, South Korea
| | - Yonghun Sung
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
| | - Jun-Koo Yi
- Gyeongbuk Livestock Research Institute, Yeongju, South Korea
| | - Myoung Ok Kim
- Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju, South Korea
| | - Zae Young Ryoo
- School of Life Science, BK21 FOUR KNU Creative Bioresearch, Kyungpook National University, Daegu, South Korea
| | - Seong-Kyoon Choi
- Core Protein Resources Center, DGIST, Daegu, South Korea.,Division of Biotechnology, DGIST, Daegu, South Korea
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Zhang Y, Jing Y, Pan R, Ding K, Chen R, Meng Q. Mechanisms of Cancer Inhibition by Local Anesthetics. Front Pharmacol 2021; 12:770694. [PMID: 34950031 PMCID: PMC8688799 DOI: 10.3389/fphar.2021.770694] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 11/15/2021] [Indexed: 01/17/2023] Open
Abstract
The use of local anesthetics during surgical treatment of cancer patients is an important part of perioperative analgesia. In recent years, it has been showed that local anesthetics can directly or indirectly affect the progression of tumors. In vitro and in vivo studies have demonstrated that local anesthetics reduced cancer recurrence. The etiology of this effect is likely multifactorial. Numerous mechanisms were proposed based on the local anesthetic used and the type of cancer. Mechanisms center on NaV1.5 channels, Ras homolog gene family member A, cell cycle, endothelial growth factor receptor, calcium Influx, microRNA and mitochondrial, in combination with hyperthermia and transient receptor potential melastatin 7 channels. Local anesthetics significantly decrease the proliferation of cancers, including ovarian, breast, prostate, thyroid, colon, glioma, and histiocytic lymphoma cell cancers, by activating cell death signaling and decreasing survival pathways. We also summarized clinical evidence and randomized trial data to confirm that local anesthetics inhibited tumor progression.
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Affiliation(s)
- Yiguo Zhang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yixin Jing
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Rui Pan
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ke Ding
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Rong Chen
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Anesthesiology, East Hospital, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qingtao Meng
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Anesthesiology, East Hospital, Renmin Hospital of Wuhan University, Wuhan, China
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Cutliffe AL, McKenna SL, Chandrashekar DS, Ng A, Devonshire G, Fitzgerald RC, O’Donovan TR, Mackrill JJ. Alterations in the Ca2+ toolkit in oesophageal adenocarcinoma. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2021; 2:543-575. [PMID: 36046118 PMCID: PMC9400700 DOI: 10.37349/etat.2021.00063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 10/08/2021] [Indexed: 11/24/2022] Open
Abstract
Aim: To investigate alterations in transcription of genes, encoding Ca2+ toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene expression, tumor grade, nodal-metastatic stage, and patient survival. Methods: The expression of 275 transcripts, encoding components of the Ca2+ toolkit, was analyzed in two OAC datasets: the Cancer Genome Atlas [via the University of Alabama Cancer (UALCAN) portal] and the oesophageal-cancer, clinical, and molecular stratification [Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS)] dataset. Effects of differential expression of these genes on patient survival were determined using Kaplan-Meier log-rank tests. OAC grade- and metastatic-stage status was investigated for a subset of genes. Adjustment for the multiplicity of testing was made throughout. Results: Of the 275 Ca2+-toolkit genes analyzed, 75 displayed consistent changes in expression between OAC and normal tissue in both datasets. The channel-encoding genes, N-methyl-D-aspartate receptor 2D (GRIN2D), transient receptor potential (TRP) ion channel classical or canonical 4 (TRPC4), and TRP ion channel melastatin 2 (TRPM2) demonstrated the greatest increase in expression in OAC in both datasets. Nine genes were consistently upregulated in both datasets and were also associated with improved survival outcomes. The 6 top-ranking genes for the weighted significance of altered expression and survival outcomes were selected for further analysis: voltage-gated Ca2+ channel subunit α 1D (CACNA1D), voltage-gated Ca2+ channel auxiliary subunit α2 δ4 (CACNA2D4), junctophilin 1 (JPH1), acid-sensing ion channel 4 (ACCN4), TRPM5, and secretory pathway Ca2+ ATPase 2 (ATP2C2). CACNA1D, JPH1, and ATP2C2 were also upregulated in advanced OAC tumor grades and nodal-metastatic stages in both datasets. Conclusions: This study has unveiled alterations of the Ca2+ toolkit in OAC, compared to normal tissue. Such Ca2+ signalling findings are consistent with those from studies on other cancers. Genes that were consistently upregulated in both datasets might represent useful markers for patient diagnosis. Genes that were consistently upregulated, and which were associated with improved survival, might be useful markers for patient outcome. These survival-associated genes may also represent targets for the development of novel chemotherapeutic agents.
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Affiliation(s)
- Alana L. Cutliffe
- Department of Physiology, University College Cork, BioSciences Institute, T12 YT20 Cork, Ireland
| | - Sharon L. McKenna
- Cancer Research, UCC, Western Gateway Building, University College Cork, T12 XF62 Cork, Ireland
| | - Darshan S. Chandrashekar
- Department of Pathology, Molecular & Cellular, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Alvin Ng
- Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Robinson Way, CB2 0RE Cambridge, UK
| | - Ginny Devonshire
- Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Robinson Way, CB2 0RE Cambridge, UK
| | - Rebecca C. Fitzgerald
- Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Robinson Way, CB2 0RE Cambridge, UK
| | - Tracey R. O’Donovan
- Cancer Research, UCC, Western Gateway Building, University College Cork, T12 XF62 Cork, Ireland
| | - John J. Mackrill
- Department of Physiology, University College Cork, BioSciences Institute, T12 YT20 Cork, Ireland
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Verigos J, Kordias D, Papadaki S, Magklara A. Transcriptional Profiling of Tumorspheres Reveals TRPM4 as a Novel Stemness Regulator in Breast Cancer. Biomedicines 2021; 9:biomedicines9101368. [PMID: 34680485 PMCID: PMC8533210 DOI: 10.3390/biomedicines9101368] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) have been implicated in the development of chemoresistance, tumor recurrence and metastasis in breast cancer, thus emerging as a promising target for novel therapies. To identify novel stemness regulators that could potentially be targeted in luminal ER+ tumors, we performed RNA-sequencing (RNA-seq) in MCF-7 adherent monolayer cells and tumorspheres enriched in breast CSCs (bCSCs). We identified 1421 differentially expressed genes (DEGs), with 923 of them being upregulated and 498 downregulated in tumorspheres. Gene ontology and pathway enrichment analyses revealed that distinct gene networks underlie the biology of the two cell systems. We selected the transient receptor potential cation channel subfamily M member 4 (TRPM4) gene that had not been associated with cancer stemness before for further investigation. We confirmed that TRPM4 was overexpressed in tumorspheres and showed that its knock-down affected the stemness properties of bCSCs in vitro. TRPM4 inhibition revealed potential anti-tumor effects by directly targeting the bCSC subpopulation. We suggest that TRPM4 plays a key role in stemness mediation, and its inhibition may represent a novel therapeutic modality against bCSCs contributing in the improvement of breast cancer treatments.
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Affiliation(s)
- John Verigos
- Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology, 45110 Ioannina, Greece; (J.V.); (D.K.)
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece;
| | - Dimitris Kordias
- Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology, 45110 Ioannina, Greece; (J.V.); (D.K.)
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece;
| | - Styliani Papadaki
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece;
| | - Angeliki Magklara
- Institute of Molecular Biology and Biotechnology-Foundation for Research and Technology, 45110 Ioannina, Greece; (J.V.); (D.K.)
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece;
- Institute of Biosciences, University Research Center of Ioannina (URCI), 45110 Ioannina, Greece
- Correspondence:
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Ali Shah SM, Ou YY. TRP-BERT: Discrimination of transient receptor potential (TRP) channels using contextual representations from deep bidirectional transformer based on BERT. Comput Biol Med 2021; 137:104821. [PMID: 34508974 DOI: 10.1016/j.compbiomed.2021.104821] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 11/16/2022]
Abstract
Transient receptor potential (TRP) channels are non-selective cation channels that act as ion channels and are primarily found on the plasma membrane of numerous animal cells. These channels are involved in the physiology and pathophysiology of a wide variety of biological processes, including inhibition and progression of cancer, pain initiation, inflammation, regulation of pressure, thermoregulation, secretion of salivary fluid, and homeostasis of Ca2+ and Mg2+. Increasing evidences indicate that mutations in the gene encoding TRP channels play an essential role in a broad array of diseases. Therefore, these channels are becoming popular as potential drug targets for several diseases. The diversified role of these channels demands a prediction model to classify TRP channels from other channel proteins (non-TRP channels). Therefore, we presented an approach based on the Support Vector Machine (SVM) classifier and contextualized word embeddings from Bidirectional Encoder Representations from Transformers (BERT) to represent protein sequences. BERT is a deeply bidirectional language model and a neural network approach to Natural Language Processing (NLP) that achieves outstanding performance on various NLP tasks. We apply BERT to generate contextualized representations for every single amino acid in a protein sequence. Interestingly, these representations are context-sensitive and vary for the same amino acid appearing in different positions in the sequence. Our proposed method showed 80.00% sensitivity, 96.03% specificity, 95.47% accuracy, and a 0.56 Matthews correlation coefficient (MCC) for an independent test set. We suggest that our proposed method could effectively classify TRP channels from non-TRP channels and assist biologists in identifying new potential TRP channels.
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Affiliation(s)
- Syed Muazzam Ali Shah
- Department of Computer Science & Engineering, Yuan Ze University, Chungli, 32003, Taiwan
| | - Yu-Yen Ou
- Department of Computer Science & Engineering, Yuan Ze University, Chungli, 32003, Taiwan.
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Abstract
Transient receptor potential melastatin 8 (TRPM8) channels play a central role in the detection of environmental cold temperatures in the somatosensory system. TRPM8 is found in a subset of unmyelinated (C-type) afferents located in the dorsal root (DRG) and trigeminal ganglion (TG). Cold hypersensitivity is a common symptom of neuropathic pain conditions caused by cancer therapy, spinal cord injury, viral infection, multiple sclerosis, diabetes, or withdrawal symptoms associated with chronic morphine treatment. Therefore, TRPM8 has received great attention as a therapeutic target. However, as the activity of TRPM8 is unique in sensing cool temperature as well as warming, it is critical to understand the signaling transduction pathways that control modality-specific activity of TRPM8 in healthy versus pathological settings. This review summarizes recent advances in our understanding of the mechanisms involved in the regulation of the TRPM8 activity.
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Affiliation(s)
- Mircea Iftinca
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada
| | - Christophe Altier
- Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Diseases and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary , Calgary, Alberta, Canada
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Che X, Zhan J, Zhao F, Zhong Z, Chen M, Han R, Wang Y. Oridonin Promotes Apoptosis and Restrains the Viability and Migration of Bladder Cancer by Impeding TRPM7 Expression via the ERK and AKT Signaling Pathways. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4340950. [PMID: 34285910 PMCID: PMC8275389 DOI: 10.1155/2021/4340950] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 04/01/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Oridonin is a powerful anticancer compound found in Rabdosia rubescens. However, its potential impact on bladder cancer remains uninvestigated. In this work, we aimed to detect the anticancer effect of oridonin on bladder cancer and explore the molecular mechanisms involved. METHODS The anticancer activity of oridonin was assessed in vitro with a CCK8 assay, an annexin V-FITC apoptosis analysis, and colony formation and Transwell migration assays which were performed with the human bladder cancer cell line T24. Levels of apoptosis-related proteins, melastatin transient receptor potential channel 7 (TRPM7), and signaling molecules were examined in oridonin-treated T24 cells by western blotting or RT-PCR. Oridonin anticancer efficacy was further validated in vivo with a T24 xenograft mouse model. RESULTS Oridonin repressed the proliferative, colony-forming, and migratory capacities of T24 cells, triggered extensive apoptosis in vitro, and retarded tumor growth in vivo. Moreover, oridonin treatment significantly increased expression levels of p53 and cleaved caspase-3 and reduced expression of TRPM7, p-AKT, and p-ERK. CONCLUSION Oridonin exhibited outstanding antiproliferative and antimigratory effects on bladder cancer, and these effects were at least partially associated with targeting of TRPM7 through inactivation of the ERK and AKT signaling pathways. These findings provide insight for the clinical application of oridonin in bladder cancer prevention.
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Affiliation(s)
- Xianping Che
- Department of Urology, The Second Affiliated Hospital of Hainan Medical University, 570311 Hainan, China
| | - Jiangtao Zhan
- Department of Urology, The Second Affiliated Hospital of Hainan Medical University, 570311 Hainan, China
| | - Fan Zhao
- Department of Urology, The Second Affiliated Hospital of Hainan Medical University, 570311 Hainan, China
| | - Zunhe Zhong
- Department of Urology, The Second Affiliated Hospital of Hainan Medical University, 570311 Hainan, China
| | - Mianchuan Chen
- Department of Urology, The Second Affiliated Hospital of Hainan Medical University, 570311 Hainan, China
| | - Ruifa Han
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, 300211 Tianjin, China
| | - Yi Wang
- Department of Urology, The Second Affiliated Hospital of Hainan Medical University, 570311 Hainan, China
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Bobkov D, Yudintceva N, Lomert E, Shatrova A, Kever L, Semenova S. Lipid raft integrity is required for human leukemia Jurkat T-cell migratory activity. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158917. [PMID: 33662545 DOI: 10.1016/j.bbalip.2021.158917] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 12/20/2022]
Abstract
Lipid rafts are membrane microdomains featuring high cholesterol, sphingolipid, and protein content. These microdomains recruit various receptors, ion channels, and signaling molecules for coordination of various cellular functions, including synaptic transmission, immune response, cytoskeletal organization, adhesion, and migration. Many of these processes also depend on Ca2+ intake. We have previously shown in Jurkat cells that activity of transient receptor potential vanilloid, type 6 (TRPV6) calcium channel, and TRPV6-mediated Ca2+ influx, depend on lipid raft integrity. In this study, using the transwell cell migration assay and time-lapse video microscopy with Jurkat cells, we found that lipid raft destruction was associated with: inhibited cell adhesion and migration; and decreased mean speed, maximum speed, and trajectory length. Using String Server, we constructed a Protein Interaction Network (PIN). The network indicated that TRPV6 proteins interact with the highest probability (0.9) with Src family kinase members (SFKs) involved in processes related to cell migration. Analysis of detergent-resistant membrane fractions and immunoelectron microscopy data confirmed an association in lipid rafts between TRPV6 and Lck kinase, an SFKs member. Destruction of lipid rafts led to uncoupling of TRPV6 clusters with Lck and their departure from the plasma membrane into the cytosol of the cells. Src family kinases are generally associated with their roles in tumor invasion and progression, epithelial-mesenchymal transitions, angiogenesis, and metastatic development. We suggest that a functional interaction between TRPV6 calcium channels and SFKs members in lipid rafts is one of necessary elements of migration and oncogenic signaling in leukemia cells.
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Affiliation(s)
- Danila Bobkov
- Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Prospekt, St. Petersburg 194064, Russia
| | - Natalia Yudintceva
- Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Prospekt, St. Petersburg 194064, Russia
| | - Ekaterina Lomert
- Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Prospekt, St. Petersburg 194064, Russia
| | - Alla Shatrova
- Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Prospekt, St. Petersburg 194064, Russia
| | - Lyudmila Kever
- Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Prospekt, St. Petersburg 194064, Russia
| | - Svetlana Semenova
- Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Prospekt, St. Petersburg 194064, Russia.
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Meng S, Alanazi R, Ji D, Bandura J, Luo ZW, Fleig A, Feng ZP, Sun HS. Role of TRPM7 kinase in cancer. Cell Calcium 2021; 96:102400. [PMID: 33784560 DOI: 10.1016/j.ceca.2021.102400] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 01/09/2023]
Abstract
Cancer is the second leading cause of death worldwide and accounted for an estimated 9.6 million deaths, or 1 in 6 deaths, in 2018. Despite recent advances in cancer prevention, diagnosis, and treatment strategies, the burden of this disease continues to grow with each year, with dire physical, emotional, and economic consequences for all levels of society. Classic characteristics of cancer include rapid, uncontrolled cell proliferation and spread of cancerous cells to other parts of the body, a process known as metastasis. Transient receptor potential melastatin 7 (TRPM7), a Ca2+- and Mg2+-permeable nonselective divalent cation channel defined by the atypical presence of an α-kinase within its C-terminal domain, has been implicated, due to its modulation of Ca2+ and Mg2+ influx, in a wide variety of physiological and pathological processes, including cancer. TRPM7 is overexpressed in several cancer types and has been shown to variably increase cellular proliferation, migration, and invasion of tumour cells. However, the relative contribution of TRPM7 kinase domain activity to cancer as opposed to ion flux through its channel pore remains an area of active discovery. In this review, we describe the specific role of the TRPM7 kinase domain in cancer processes as well as mechanisms of regulation and inhibition of the kinase domain.
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Affiliation(s)
- Selena Meng
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Rahmah Alanazi
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Delphine Ji
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Julia Bandura
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Zheng-Wei Luo
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Andrea Fleig
- Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine and Cancer Center at the University of Hawaii, Honolulu, HI, 96720, USA
| | - Zhong-Ping Feng
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
| | - Hong-Shuo Sun
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Pharmacology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
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Abstract
The transient receptor potential (TRP) channel superfamily is comprised of a large group of cation-permeable channels, which display an extraordinary diversity of roles in sensory signaling and are involved in plethora of animal behaviors. These channels are activated through a wide variety of mechanisms and participate in virtually every sensory modality. Modulating TRP channel activity provides an important way to regulate membrane excitability and intracellular calcium levels. This is reflected by the fact that small molecule compounds modulating different TRPs have all entered clinical trials for a variety of diseases. The role of TRPs will be further elucidated in complex diseases of the nervous, intestinal, renal, urogenital, respiratory, and cardiovascular systems in diverse therapeutic areas including pain and itch, headache, pulmonary function, oncology, neurology, visceral organs, and genetic diseases. This review focuses on recent developments in the TRP ion channel-related area and highlights evidence supporting TRP channels as promising targets for new analgesic drugs for therapeutic intervention. This review presents a variety of: (1) phylogeny aspects of TRP channels; (2) some structural and functional characteristics of TRPs; (3) a general view and short characteristics of main seven subfamilies of TRP channels; (4) the evidence for consider TRP channels as therapeutic and analgesic targets; and finally (5) further perspectives of TRP channels research.
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Jimenez I, Prado Y, Marchant F, Otero C, Eltit F, Cabello-Verrugio C, Cerda O, Simon F. TRPM Channels in Human Diseases. Cells 2020; 9:E2604. [PMID: 33291725 PMCID: PMC7761947 DOI: 10.3390/cells9122604] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 12/11/2022] Open
Abstract
The transient receptor potential melastatin (TRPM) subfamily belongs to the TRP cation channels family. Since the first cloning of TRPM1 in 1989, tremendous progress has been made in identifying novel members of the TRPM subfamily and their functions. The TRPM subfamily is composed of eight members consisting of four six-transmembrane domain subunits, resulting in homomeric or heteromeric channels. From a structural point of view, based on the homology sequence of the coiled-coil in the C-terminus, the eight TRPM members are clustered into four groups: TRPM1/M3, M2/M8, M4/M5 and M6/M7. TRPM subfamily members have been involved in several physiological functions. However, they are also linked to diverse pathophysiological human processes. Alterations in the expression and function of TRPM subfamily ion channels might generate several human diseases including cardiovascular and neurodegenerative alterations, organ dysfunction, cancer and many other channelopathies. These effects position them as remarkable putative targets for novel diagnostic strategies, drug design and therapeutic approaches. Here, we review the current knowledge about the main characteristics of all members of the TRPM family, focusing on their actions in human diseases.
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Affiliation(s)
- Ivanka Jimenez
- Faculty of Life Science, Universidad Andrés Bello, Santiago 8370186, Chile; (I.J.); (Y.P.); (F.M.); (C.C.-V.)
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8380453, Chile;
| | - Yolanda Prado
- Faculty of Life Science, Universidad Andrés Bello, Santiago 8370186, Chile; (I.J.); (Y.P.); (F.M.); (C.C.-V.)
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8380453, Chile;
| | - Felipe Marchant
- Faculty of Life Science, Universidad Andrés Bello, Santiago 8370186, Chile; (I.J.); (Y.P.); (F.M.); (C.C.-V.)
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8380453, Chile;
| | - Carolina Otero
- Faculty of Medicine, School of Chemistry and Pharmacy, Universidad Andrés Bello, Santiago 8370186, Chile;
| | - Felipe Eltit
- Vancouver Prostate Centre, Vancouver, BC V6Z 1Y6, Canada;
- Department of Urological Sciences, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
| | - Claudio Cabello-Verrugio
- Faculty of Life Science, Universidad Andrés Bello, Santiago 8370186, Chile; (I.J.); (Y.P.); (F.M.); (C.C.-V.)
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 7560484, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
| | - Oscar Cerda
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8380453, Chile;
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
| | - Felipe Simon
- Faculty of Life Science, Universidad Andrés Bello, Santiago 8370186, Chile; (I.J.); (Y.P.); (F.M.); (C.C.-V.)
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8380453, Chile;
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
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Abstract
Transient receptor potential (TRP) channels comprise a diverse family of ion channels, the majority of which are calcium permeable and show sophisticated regulatory patterns in response to various environmental cues. Early studies led to the recognition of TRP channels as environmental and chemical sensors. Later studies revealed that TRP channels mediated the regulation of intracellular calcium. Mutations in TRP channel genes result in abnormal regulation of TRP channel function or expression, and interfere with normal spatial and temporal patterns of intracellular local Ca2+ distribution. The resulting dysregulation of multiple downstream effectors, depending on Ca2+ homeostasis, is associated with hallmarks of cancer pathophysiology, including enhanced proliferation, survival and invasion of cancer cells. These findings indicate that TRP channels affect multiple events that control cellular fate and play a key role in cancer progression. This review discusses the accumulating evidence supporting the role of TRP channels in tumorigenesis, with emphasis on prostate cancer. [BMB Reports 2020; 53(3): 125-132].
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Affiliation(s)
- Dongki Yang
- Departments of Physiology, College of Medicine, Gachon University, Incheon 21999, Korea
| | - Jaehong Kim
- Departments of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea
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Various Aspects of Calcium Signaling in the Regulation of Apoptosis, Autophagy, Cell Proliferation, and Cancer. Int J Mol Sci 2020; 21:ijms21218323. [PMID: 33171939 PMCID: PMC7664196 DOI: 10.3390/ijms21218323] [Citation(s) in RCA: 214] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/28/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022] Open
Abstract
Calcium (Ca2+) is a major second messenger in cells and is essential for the fate and survival of all higher organisms. Different Ca2+ channels, pumps, or exchangers regulate variations in the duration and levels of intracellular Ca2+, which may be transient or sustained. These changes are then decoded by an elaborate toolkit of Ca2+-sensors, which translate Ca2+ signal to intracellular operational cell machinery, thereby regulating numerous Ca2+-dependent physiological processes. Alterations to Ca2+ homoeostasis and signaling are often deleterious and are associated with certain pathological states, including cancer. Altered Ca2+ transmission has been implicated in a variety of processes fundamental for the uncontrolled proliferation and invasiveness of tumor cells and other processes important for cancer progression, such as the development of resistance to cancer therapies. Here, we review what is known about Ca2+ signaling and how this fundamental second messenger regulates life and death decisions in the context of cancer, with particular attention directed to cell proliferation, apoptosis, and autophagy. We also explore the intersections of Ca2+ and the therapeutic targeting of cancer cells, summarizing the therapeutic opportunities for Ca2+ signal modulators to improve the effectiveness of current anticancer therapies.
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Pratt SJP, Lee RM, Chang KT, Hernández-Ochoa EO, Annis DA, Ory EC, Thompson KN, Bailey PC, Mathias TJ, Ju JA, Vitolo MI, Schneider MF, Stains JP, Ward CW, Martin SS. Mechanoactivation of NOX2-generated ROS elicits persistent TRPM8 Ca 2+ signals that are inhibited by oncogenic KRas. Proc Natl Acad Sci U S A 2020; 117:26008-26019. [PMID: 33020304 PMCID: PMC7584994 DOI: 10.1073/pnas.2009495117] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Changes in the mechanical microenvironment and mechanical signals are observed during tumor progression, malignant transformation, and metastasis. In this context, understanding the molecular details of mechanotransduction signaling may provide unique therapeutic targets. Here, we report that normal breast epithelial cells are mechanically sensitive, responding to transient mechanical stimuli through a two-part calcium signaling mechanism. We observed an immediate, robust rise in intracellular calcium (within seconds) followed by a persistent extracellular calcium influx (up to 30 min). This persistent calcium was sustained via microtubule-dependent mechanoactivation of NADPH oxidase 2 (NOX2)-generated reactive oxygen species (ROS), which acted on transient receptor potential cation channel subfamily M member 8 (TRPM8) channels to prolong calcium signaling. In contrast, the introduction of a constitutively active oncogenic KRas mutation inhibited the magnitude of initial calcium signaling and severely blunted persistent calcium influx. The identification that oncogenic KRas suppresses mechanically-induced calcium at the level of ROS provides a mechanism for how KRas could alter cell responses to tumor microenvironment mechanics and may reveal chemotherapeutic targets for cancer. Moreover, we find that expression changes in both NOX2 and TRPM8 mRNA predict poor clinical outcome in estrogen receptor (ER)-negative breast cancer patients, a population with limited available treatment options. The clinical and mechanistic data demonstrating disruption of this mechanically-activated calcium pathway in breast cancer patients and by KRas activation reveal signaling alterations that could influence cancer cell responses to the tumor mechanical microenvironment and impact patient survival.
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Affiliation(s)
- Stephen J P Pratt
- Program in Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201;
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Rachel M Lee
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Katarina T Chang
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Erick O Hernández-Ochoa
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - David A Annis
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Eleanor C Ory
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Keyata N Thompson
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Patrick C Bailey
- Program in Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Trevor J Mathias
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Julia A Ju
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Michele I Vitolo
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Martin F Schneider
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Joseph P Stains
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201
| | - Christopher W Ward
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201
- School of Nursing, University of Maryland, Baltimore, MD 21201
| | - Stuart S Martin
- Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201;
- Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201
- Marlene and Stewart Greenebaum National Cancer Institute Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201
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Ma C, Li X, Chen J, Li Z, Guan J, Li Y, Yin S, Shi Y. Association Analysis Between Common Variants of the TRPM1 Gene and Three Mental Disorders in the Han Chinese Population. Genet Test Mol Biomarkers 2020; 24:649-657. [PMID: 33001715 PMCID: PMC7585623 DOI: 10.1089/gtmb.2019.0096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Objective: Our study was designed to determine if the TRPM1 gene is associated with any of three mental disorders. The project included a cross disorder meta-analysis and association analysis including 141701 cases and 175248 controls. Materials and Methods: We genotyped eight tag single nucleotide polymorphisms (SNPs) in 1248 unrelated schizophrenia (SCZ) patients, 1056 major depressive disorder patients, 1344 bipolar disorder patients, and 1248 normal controls. We then performed a meta-analysis of 10 GWASs to identify common genetic factors among these three mental disorders. Finally, we performed a meta-analysis of six GWASs to explore the role of rs10162727 in SCZ. Result: Although two haplotypes of the TRPM1 gene, rs1035706-rs10162727 and rs10162727-rs3784599, were identified in the control group, as well as all three disease groups, none of the eight tag SNP associations remained significant after correction for multiple tests. In this cross-disorder meta-analysis of the three diseases, none of the tag SNPs were confirmed to be common among the diseases. In addition, in the meta-analysis conducted for the rs10162727 locus in SCZ, there was no significant association (p-value = 0.84, odds ratio = 1.02 [95% CI = 0.87-1.19]). Conclusion: In the Han Chinese population, no significant evidence was found linking variants of the TRPM1 gene with any of the mental disorders examined.
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Affiliation(s)
- Chuanchuan Ma
- Department of Biology, School of Life Science, Anhui Medical University, Hefei, China
| | - Xiuli Li
- Department of Biology, School of Life Science, Anhui Medical University, Hefei, China
| | - Jianhua Chen
- Department of Biology, School of Life Science, Anhui Medical University, Hefei, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Department of Otolaryngology, Therapy Center for Obstructive Sleep Apnea, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
| | - Zhiqiang Li
- Department of Biology, School of Life Science, Anhui Medical University, Hefei, China
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Department of Otolaryngology, Therapy Center for Obstructive Sleep Apnea, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
- The Affiliated Hospital of Qingdao University, The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, People's Republic of China
| | - Jian Guan
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Department of Otolaryngology, Therapy Center for Obstructive Sleep Apnea, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
| | - Yigang Li
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Shankai Yin
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Department of Otolaryngology, Therapy Center for Obstructive Sleep Apnea, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
| | - Yongyong Shi
- Department of Biology, School of Life Science, Anhui Medical University, Hefei, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China
- Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Department of Otolaryngology, Therapy Center for Obstructive Sleep Apnea, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai, China
- The Affiliated Hospital of Qingdao University, The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, People's Republic of China
- Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education) and the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, People's Republic of China
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