|
1
|
Zou Z, Zhong L. Anaplastic thyroid cancer: Genetic roles, targeted therapy, and immunotherapy. Genes Dis 2025; 12:101403. [PMID: 40271195 PMCID: PMC12018003 DOI: 10.1016/j.gendis.2024.101403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/02/2024] [Accepted: 08/02/2024] [Indexed: 04/25/2025] Open
Abstract
Anaplastic thyroid cancer (ATC) stands as the most formidable form of thyroid malignancy, presenting a persistent challenge in clinical management. Recent years have witnessed a gradual unveiling of the intricate genetic underpinnings governing ATC through next-generation sequencing. The emergence of this genetic landscape has paved the way for the exploration of targeted therapies and immunotherapies in clinical trials. Despite these strides, the precise mechanisms governing ATC pathogenesis and the identification of efficacious treatments demand further investigation. Our comprehensive review stems from an extensive literature search focusing on the genetic implications, notably the pivotal MAPK and PI3K-AKT-mTOR signaling pathways, along with targeted therapies and immunotherapies in ATC. Moreover, we screen and summarize the advances and challenges in the current diagnostic approaches for ATC, including the invasive tissue sampling represented by fine needle aspiration and core needle biopsy, immunohistochemistry, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography. We also investigate enormous studies on the prognosis of ATC and outline independent prognostic factors for future clinical assessment and therapy for ATC. By synthesizing this literature, we aim to encapsulate the evolving landscape of ATC oncology, potentially shedding light on novel pathogenic mechanisms and avenues for therapeutic exploration.
Collapse
Affiliation(s)
- Zhao Zou
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Linhong Zhong
- Chongqing Key Laboratory of Ultrasound Molecular Imaging, Institute of Ultrasound Imaging and Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| |
Collapse
|
|
2
|
Cabanillas ME, Dadu R, Ferrarotto R, Gule-Monroe M, Liu S, Fellman B, Williams MD, Zafereo M, Wang JR, Lu C, Ning M, McKinley BA, Woodman SE, Duose D, Gunn GB, Busaidy NL. Anti-Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial. JAMA Oncol 2024; 10:1672-1680. [PMID: 39446377 PMCID: PMC11581602 DOI: 10.1001/jamaoncol.2024.4729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 07/08/2024] [Indexed: 11/24/2024]
Abstract
Importance Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors. Objective To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS). Design, Setting, and Participants A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023. Interventions Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab. Main Outcomes and Measures The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months. Results Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable [NE]), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively. Conclusions and Relevance In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS. Trial Registration ClinicalTrials.gov Identifier: NCT03181100.
Collapse
Affiliation(s)
- Maria E. Cabanillas
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston
| | - Ramona Dadu
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston
| | - Renata Ferrarotto
- Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer, Houston
| | - Maria Gule-Monroe
- Department of Neuroradiology, The University of Texas MD Anderson Cancer, Houston
| | - Suyu Liu
- Department of Biostatistics, The University of Texas MD Anderson Cancer, Houston
| | - Bryan Fellman
- Department of Biostatistics, The University of Texas MD Anderson Cancer, Houston
| | | | - Mark Zafereo
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer, Houston
| | - Jennifer R. Wang
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer, Houston
| | - Charles Lu
- Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer, Houston
| | - Matthew Ning
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer, Houston
| | - Brian A. McKinley
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer, Houston
| | - Scott E. Woodman
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer, Houston
| | - Dzifa Duose
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston
| | - Gary B. Gunn
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer, Houston
| | - Naifa L. Busaidy
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston
| |
Collapse
|
|
3
|
Loganathan T, George Priya Doss C. Biomarker identification of medullary thyroid carcinoma from gene expression profiles considering without-treatment and with-treatment studies-A bioinformatics approach. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:367-396. [PMID: 39059991 DOI: 10.1016/bs.apcsb.2023.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular thyroid gland cells. In both hereditary MTC and sporadic forms, genetic changes result in fundamental changes, and prognosis and mutational status are highly correlated. In this work, biomarker genes (DEGs and DEmiRNAs) for MTC will be computationally identified in order to help in their diagnosis and treatment. The gene expression profiles of two different types of studies, namely without-treatment (wo-trt) and with-treatment (w-trt), are considered for discovering biomarkers. The datasets were retrieved from the GEO database, and the DEGs and DEmiRNAs were analyzed using ExpressAnalyst and GEO2R. The functional analysis of DEGs and DEmiRNAs was performed, and most of the pathways enriched related to thyroid oncological pathways such as MAPK pathway,mTOR pathway, and PI3K-AKT Signaling pathway. Through this conclusion, the RET gene was upregulated wo-trt; the dinaciclib treatment RET gene was down-regulated computationally. To optimize the therapeutic targeting of RET, greater research into the mechanisms regulating RET transcription is necessary.
Collapse
Affiliation(s)
- Tamizhini Loganathan
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - C George Priya Doss
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
| |
Collapse
|
|
4
|
Limberg J, Egan CE, Gray KD, Singh M, Loewenstein Z, Yang Y, Riascos MC, Al Asadi H, Safe P, El Eshaky S, Liang H, Ullmann TM, Wang W, Li W, Zhang T, Xiang J, Stefanova D, Jin MM, Zarnegar R, Fahey TJ, Min IM. Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma. Mol Cancer Res 2023; 21:397-410. [PMID: 36790391 PMCID: PMC10159921 DOI: 10.1158/1541-7786.mcr-21-0832] [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: 10/05/2021] [Revised: 03/25/2022] [Accepted: 01/11/2023] [Indexed: 02/16/2023]
Abstract
A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient-derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in patients with differentiated thyroid cancer. Analysis of tumor RNA expression in patients with poorly differentiated thyroid cancer and ATC also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer. IMPLICATIONS Dual inhibition of BRAF and JAK/STAT signaling pathway is a potential therapeutic treatment for anticancer activity and to overcome drug resistance to BRAFi in thyroid cancer.
Collapse
Affiliation(s)
- Jessica Limberg
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Caitlin E. Egan
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | | | - Mandeep Singh
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | | | - Yanping Yang
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | | | - Hala Al Asadi
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Parima Safe
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Steve El Eshaky
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Heng Liang
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | | | - Weibin Wang
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Wei Li
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Tuo Zhang
- Genomics Resource Core Facility, Weill Cornell Medicine, New York, NY 10065
| | - Jenny Xiang
- Genomics Resource Core Facility, Weill Cornell Medicine, New York, NY 10065
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065
| | | | - Moonsoo M. Jin
- Department of Radiology, Weill Cornell Medicine, New York, NY 10065
| | - Rasa Zarnegar
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Thomas J. Fahey
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| | - Irene M. Min
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065
| |
Collapse
|
|
5
|
Xie F, Yan L, Li YM, Lan Y, Xiao J, Zhang MB, Jin Z, Zhang Y, Tian XQ, Zhu YQ, Li ZP, Luo YK. Targeting Diagnosis of High-Risk Papillary Thyroid Carcinoma Using Ultrasound Contrast Agent With the BRAF V600E Mutation: An Experimental Study. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2022; 41:2789-2802. [PMID: 35229905 DOI: 10.1002/jum.15967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/14/2022] [Accepted: 02/02/2022] [Indexed: 06/14/2023]
Abstract
OBJECTIVE High-risk papillary thyroid carcinoma (PTC) patients with BRAF mutation have lymph node and distant metastases and poor prognosis. Therefore, this study aims to develop a targeted ultrasound contrast agent for the BRAFV600E mutation to screen high-risk PTC at early stage. METHODS The targeted lipid nanobubbles carrying BRAFV600E antibody were prepared using thin film hydration-sonication and avidin-biotin binding methods. The physicochemical properties and stability of the targeted nanobubbles were detected by transmission electron microscopy, atomic force microscopy, and confocal laser scanning microscopy. The target binding abilities of the targeted nanobubbles in the PTC cells (B-CPAP) overexpressed mutant BRAFV600E were evaluated by immunofluorescence staining, quantitative real-time polymerase chain reaction, western blot, and fluorescence microscopy. After PTC tumor models overexpressed mutant BRAFV600E were established, the enhanced images of targeted lipid nanobubbles and untargeted lipid nanobubbles on PTC tumors in nude mice were observed using contrast-enhanced ultrasound imaging. RESULTS The targeted lipid nanobubbles revealed uniform, round morphology, and good stability with a nanoscale size. Besides, BRAFV600E monoclonal antibody was observed to be combined on the surface of lipid nanobubbles. Furthermore, the targeted nanobubbles had a good targeting diagnosis ability in PTC cells with BRAFV600E overexpression. Moreover, the targeted nanobubbles had better ultrasound enhancement and peak intensity of the time-intensity curve (P < .001) in PTC tumors with BRAFV600E overexpression as compared to the untargeted lipid nanobubbles. CONCLUSION The targeted lipid nanobubbles carrying BRAFV600E antibody could be regarded as a potential targeted ultrasound contrast agent for the diagnosis of high-risk PTC.
Collapse
Affiliation(s)
- Fang Xie
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Lin Yan
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Yi-Ming Li
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Yu Lan
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Jing Xiao
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Ming-Bo Zhang
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Zhuang Jin
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Ying Zhang
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Xiao-Qi Tian
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Ya-Qiong Zhu
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| | - Zhi-Ping Li
- Pharmacology Research Department, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Yu-Kun Luo
- Department of Ultrasound, The First Medical Center of PLA General Hospital, Beijing, China
| |
Collapse
|
|
6
|
Zhang Y, Xing Z, Liu T, Tang M, Mi L, Zhu J, Wu W, Wei T. Targeted therapy and drug resistance in thyroid cancer. Eur J Med Chem 2022; 238:114500. [DOI: 10.1016/j.ejmech.2022.114500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022]
|
|
7
|
Zerfaoui M, Tsumagari K, Toraih E, Errami Y, Ruiz E, Elaasar MSM, Krzysztof M, Sholl AB, Magdeldin S, Soudy M, Abd Elmageed ZY, Boulares AH, Kandil E. Nuclear interaction of Arp2/3 complex and BRAF V600E promotes aggressive behavior and vemurafenib resistance of thyroid cancer. Am J Cancer Res 2022; 12:3014-3033. [PMID: 35968344 PMCID: PMC9360225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/12/2022] [Indexed: 04/22/2023] Open
Abstract
The presence of mutant BRAF V600E correlates with the risk of recurrence in papillary thyroid cancer (PTC) patients. However, not all PTC patients with BRAF V600E are associated with poor prognosis. Thus, understanding the mechanisms by which certain PTC patients with nuclear BRAF V600E become aggressive and develop resistance to a selective BRAF inhibitor, PLX-4032, is urgently needed. The effect of nuclear localization of BRAFV600E using in vitro studies, xenograft mouse-model and human tissues was evaluated. PTC cells harboring a nuclear localization signal (NLS) of BRAFV600E were established and examined in nude mice implanted with TPC1-NLS-BRAFV600E cells followed by PLX-4032 treatment. Immunohistochemical (IHC) analysis was performed on 100 PTC specimens previously confirmed that they have BRAFV600E mutations. Our results demonstrate that 21 of 100 (21%) PTC tissues stained with specific BRAFV600E antibody had nuclear staining with more aggressive features compared to their cytosolic counterparts. In vitro studies show that BRAFV600E is transported between the nucleus and the cytosol through CRM1 and importin (α/β) system. Sequestration of BRAFV600E in the cytosol sensitized resistant cells to PLX-4032, whereas nuclear BRAFV600E was associated with aggressive phenotypes and developed drug resistance. Proteomic analysis revealed Arp2/3 complex members, actin-related protein 2 (ACTR2 aliases ARP2) and actin-related protein 3 (ACTR3 aliases ARP3), as the most enriched nuclear BRAFV600E partners. ACTR3 was highly correlated to lymph node stage and extrathyroidal extension and was validated with different functional assays. Our findings provide new insights into the clinical utility of the nuclear BRAFV600E as a prognostic marker for PTC aggressiveness and determine the efficacy of selective BRAFV600E inhibitor treatment which opens new avenues for future treatment options.
Collapse
Affiliation(s)
- Mourad Zerfaoui
- Department of Surgery, Tulane University School of MedicineUSA
| | - Koji Tsumagari
- Department of Surgery, Tulane University School of MedicineUSA
| | - Eman Toraih
- Department of Surgery, Tulane University School of MedicineUSA
| | - Youssef Errami
- Department of Surgery, Tulane University School of MedicineUSA
| | - Emmanuelle Ruiz
- Department of Surgery, Tulane University School of MedicineUSA
| | | | - Moroz Krzysztof
- Department of Pathology, Tulane University School of MedicineUSA
| | - Andrew B Sholl
- Department of Otolaryngology, Tulane University School of MedicineUSA
| | - Sameh Magdeldin
- Proteomics Research Program Unit, Basic Research Department, Children Cancer Hospital CairoEgypt
- Department of Physiology, Faculty of Veterinary Medicine, Suez Canal UniversityIsmailia 41522, Egypt
| | - Mohamed Soudy
- Proteomics Research Program Unit, Basic Research Department, Children Cancer Hospital CairoEgypt
| | - Zakaria Y Abd Elmageed
- Department of Surgery, Tulane University School of MedicineUSA
- Department of Pharmacology, Edward Via College of Osteopathic Medicine, University of LouisianaMonroe, USA
| | - A Hamid Boulares
- Department of Pharmacology, LSU Health Sciences CenterNew Orleans, LA, USA
| | - Emad Kandil
- Department of Surgery, Tulane University School of MedicineUSA
| |
Collapse
|
|
8
|
Ye R, Liu D, Guan H, AiErken N, Fang Z, Shi Y, Zhang Y, Wang S. AHNAK2 promotes thyroid carcinoma progression by activating the NF-κB pathway. Life Sci 2021; 286:120032. [PMID: 34627772 DOI: 10.1016/j.lfs.2021.120032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 10/03/2021] [Accepted: 10/03/2021] [Indexed: 02/06/2023]
Abstract
Thyroid carcinoma metastasis is the main reason for treatment failure; therefore, understanding the regulatory mechanisms of thyroid carcinoma metastasis is critical to treat patients with thyroid carcinoma. The present study aimed to investigate the role of AHNAK Nucleoprotein 2 (AHNAK2) in thyroid carcinoma metastasis. AHNAK2 was found to be upregulated in thyroid carcinoma tissues, especially in metastatic thyroid carcinoma tissues. Patients with high AHNAK2 expression had poor prognosis. AHNAK2 knockdown inhibited thyroid carcinoma migration, invasion, and metastasis. Mechanistic analysis showed that AHNAK2 knockdown reduced thyroid carcinoma progression by inhibiting nuclear factor kappa B (NF-κB) pathway activity. The results identified a novel target to treat metastatic thyroid carcinoma.
Collapse
Affiliation(s)
- Runyi Ye
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dongwei Liu
- Department of General Practice，The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China
| | - Hongyu Guan
- Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - NiJiati AiErken
- Department of Breast and Thyroid Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, ShenZhen 518107, China
| | - Zeng Fang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yawei Shi
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yunjian Zhang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Shenming Wang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| |
Collapse
|
|
9
|
Synergistic effect of metformin and vemurufenib (PLX4032) as a molecular targeted therapy in anaplastic thyroid cancer: an in vitro study. Mol Biol Rep 2021; 48:7443-7456. [PMID: 34716862 DOI: 10.1007/s11033-021-06762-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 09/22/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Survival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC. Hence the rationale of the study is to explore combinational therapeutic effect to improve the efficacy of vemurafenib along with metformin. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer. METHODS AND RESULTS Using iGEMDock software, a protein-ligand interaction was successful between Metformin and TSHR (receptor present in the thyroid follicular cells). Our study demonstrates that combination of vemurufenib with metformin has synergistic anti-cancer effects which was evaluated through MTT assay (cytotoxicity), colony formation assay (antiproliferation evaluation) and suppressed the progression of ATC cells growth by inducing significant apoptosis, proven by Annexin V-FITC assay (Early Apoptosis Detection). Downregulation of ERK signaling, upregulation of AMPK pathway and precision in epithelial-mesenchymal transition (EMT) pathway which were assessed by RT-PCR and Western blot provide the evidence that the combination of drugs involved in the precision of altered molecular signaling Further our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. Our study for the first time explored cAMP signaling in ATC wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment. CONCLUSION To conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.
Collapse
|
|
10
|
Hicks HM, McKenna LR, Espinoza VL, Pozdeyev N, Pike LA, Sams SB, LaBarbera D, Reigan P, Raeburn CD, E Schweppe R. Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo. Mol Carcinog 2021; 60:201-212. [PMID: 33595872 DOI: 10.1002/mc.23284] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 11/09/2022]
Abstract
Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF-directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single-agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF-mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients.
Collapse
Affiliation(s)
- Hannah M Hicks
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Logan R McKenna
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Surgery, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Veronica L Espinoza
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nikita Pozdeyev
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Division of Bioinformatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Laura A Pike
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Sharon B Sams
- Department of Pathology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Daniel LaBarbera
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Philip Reigan
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Christopher D Raeburn
- Department of Surgery, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Rebecca E Schweppe
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Pathology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| |
Collapse
|
|
11
|
Pozdeyev N, Rose MM, Bowles DW, Schweppe RE. Molecular therapeutics for anaplastic thyroid cancer. Semin Cancer Biol 2020; 61:23-29. [PMID: 31991166 DOI: 10.1016/j.semcancer.2020.01.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 02/07/2023]
Abstract
Anaplastic thyroid cancer (ATC) represents one of the most lethal human cancers and although this tumor type is rare, ATC accounts for the majority of deaths from thyroid cancer. Due to the rarity of ATC, a comprehensive genomic characterization of this tumor type has been challenging, and thus the development of new therapies has been lacking. To date, there is only one mutation-driven targeted therapy for BRAF-mutant ATC. Recent genomic studies have used next generation sequencing to define the genetic landscape of ATC in order to identify new therapeutic targets. Together, these studies have confirmed the role of oncogenic mutations of MAPK pathway as key drivers of differentiated thyroid cancer (BRAF, RAS), and that additional genetic alterations in the PI3K pathway, TP53, and the TERT promoter are necessary for anaplastic transformation. Recent novel findings have linked the high mutational burden associated with ATC with mutations in the Mismatch Repair (MMR) pathway and overactivity of the AID/APOBEC family of cytidine deaminases. Additional novel mutations include cell cycle genes, SWI/SNF chromatin remodeling complex, and histone modification genes. Mutations in RAC1 were also identified in ATC, which have important implications for BRAF-directed therapies. In this review, we summarize these novel findings and the new genetic landscape of ATC. We further discuss the development of therapies targeting these pathways that are being tested in clinical and preclinical studies.
Collapse
Affiliation(s)
- Nikita Pozdeyev
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Aurora, CO, USA; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, Aurora, CO, USA
| | - Madison M Rose
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Aurora, CO, USA
| | - Daniel W Bowles
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rebecca E Schweppe
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Aurora, CO, USA.
| |
Collapse
|
|
12
|
VCAM-1 Upregulation Contributes to Insensitivity of Vemurafenib in BRAF-Mutant Thyroid Cancer. Transl Oncol 2020; 13:441-451. [PMID: 31911278 PMCID: PMC6948368 DOI: 10.1016/j.tranon.2019.10.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 10/11/2019] [Accepted: 10/14/2019] [Indexed: 12/13/2022] Open
Abstract
Vemurafenib, an inhibitor of mutant BRAF activity, is a promising anticancer agent for patients with BRAF-mutant metastatic melanoma. However, it is less effective in BRAF-mutant thyroid cancer, and the reason for this discrepancy is not yet fully elucidated. By RNA sequencing analysis, we identified vascular cell adhesion molecular-1 (VCAM-1) to be highly upregulated in both time- and dose-dependent manners during BRAF inhibition (BRAFi) in a BRAF-mutant papillary thyroid cancer cell line (BCPAP). Cell cytotoxicity and apoptosis assays showed that knockdown of the induced VCAM-1 in BCPAP cells augmented the antitumor effects of vemurafenib, with decreased IC50 values of 1.4 to 0.8 μM. Meanwhile, overexpression of VCAM-1 in a BRAF-mutant anaplastic thyroid cancer cell line (FRO) reduced the sensitivity to vemurafenib, with increased IC50 values of 1.9 to 5.8 μM. Further investigation showed that PI3K-Akt-mTOR pathway was activated during BRAFi. Co-treatment with Akt signaling inhibitor MK2206 decreased the induced expression of VCAM-1 during BRAFi. This combination further improved the efficacy of vemurafenib. Moreover, VCAM-1 promoted migration and invasion in thyroid cancer cells in vitro, which was also indicated in thyroid cancer patients. The present study is the first to demonstrate that VCAM-1 is upregulated in thyroid cancer cells treated with vemurafenib and contributes to vemurafenib resistance in BRAF-mutant thyroid cancer cells. Targeting the PI3K-Akt-mTOR pathway–mediated VCAM-1 response may be an alternative strategy to sensitize BRAF-mutant thyroid cancers to vemurafenib.
Collapse
|
|
13
|
Pilli T, Cantara S, Marzocchi C, Pacini F, Prabhakar BS, Castagna MG. Vemurafenib may overcome TNF-related apoptosis-inducing ligand (TRAIL) resistance in anaplastic thyroid cancer cells. Endocrine 2020; 67:117-123. [PMID: 31377969 DOI: 10.1007/s12020-019-02028-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE Anaplastic thyroid cancer (ATC) is rare but with poor prognosis. TRAIL can selectively induce apoptosis in cancer cells; however, resistance is quite common. Aim of our study was to evaluate TRAIL-induced apoptosis in ATC-derived cell lines, in vitro and in vivo, and the effect of combination with tyrosine kinase inhibitors (TKIs) selective for BRAF (vemurafenib) or Akt (MK-2206). METHODS Four ATC-derived cell lines were used: C643, CAL62, HTh7, with activating mutation of RAS and copy gain of PI3K (HTh7) and, 8505C with activating mutation of BRAF. Cells were treated with TRAIL alone or in combination with vemurafenib or MK-2206. The pro-apoptotic effect of TRAIL alone or combined with TKIs was, also, evaluated in two mouse xenograft models (HTh7 and 8505C). RESULTS C643, CAL62, and HTh7 cells were sensitive to TRAIL-induced apoptosis, whereas 8505C cells were resistant. Both in vitro and in vivo vemurafenib was able to increase the TRAIL-induced apoptosis in 8505C cells causing a slower tumor growth in 8505C xenograft compared to placebo, while MK-2206 did not have any additive effect on TRAIL treatment in HTh7 model. CONCLUSIONS TRAIL is a promising therapeutic agent in ATC and in case of resistance vemurafenib may be a valid complementary therapy.
Collapse
Affiliation(s)
- Tania Pilli
- Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy
| | - Silvia Cantara
- Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy
| | - Carlotta Marzocchi
- Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy
| | - Furio Pacini
- Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA
| | - Maria Grazia Castagna
- Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy.
| |
Collapse
|
|
14
|
Wang RG, Zhang D, Zhao CH, Wang QL, Qu H, He QS. FKBP10 functioned as a cancer-promoting factor mediates cell proliferation, invasion, and migration via regulating PI3K signaling pathway in stomach adenocarcinoma. Kaohsiung J Med Sci 2019; 36:311-317. [PMID: 31868996 DOI: 10.1002/kjm2.12174] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 12/02/2019] [Indexed: 11/08/2022] Open
Abstract
As documented, the expression, biological roles, and prognostic significance of FKBP10 in stomach adenocarcinoma (STAD) have not been investigated till now. This drives us to detect the biological roles and clinical significance of FKBP10 in STAD. The expression level of FKBP10 was measured based on the data obtained from the TCGA, ONCOMINE, and GEPIA databases, and STAD cell lines. Through in vitro experiments, cell behaviors were investigated to evaluate the effects of FKBP10 on STAD. Moreover, the PI3K-AKT signaling pathway was measured. Relying on the data of TCGA, ONCOMINE, and GEPIA databases, and cancer cell lines, FKBP10 was up-regulated in STAD when compared with normals. The patients with low expression of FKBP10 had higher survival rate than those with high FKBP10 expression. After knockdown of FKBP10 in AGS cells, cell vitality, colony formation ability, and the migratory and invasive potential were inhibited. Western blotting analysis exhibited that knockdown of FKBP10 significantly reduced the expression level of p-AKT, and p-PI3K, but it did not influence the total expression level of AKT, and PI3K. FKBP10 might serve as a crucial player in gastric cancer, and targeting FKBP10 might provide clinical utility in gastric cancer in future.
Collapse
Affiliation(s)
- Ruo-Gu Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Dan Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Chun-Hong Zhao
- Central Lab, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Qi-Long Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Hui Qu
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Qing-Si He
- Department of Gastrointestinal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
| |
Collapse
|
|
15
|
Jin Y, Liu M, Sa R, Fu H, Cheng L, Chen L. Mouse models of thyroid cancer: Bridging pathogenesis and novel therapeutics. Cancer Lett 2019; 469:35-53. [PMID: 31589905 DOI: 10.1016/j.canlet.2019.09.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/25/2019] [Accepted: 09/30/2019] [Indexed: 12/27/2022]
Abstract
Due to a global increase in the incidence of thyroid cancer, numerous novel mouse models were established to reveal thyroid cancer pathogenesis and test promising therapeutic strategies, necessitating a comprehensive review of translational medicine that covers (i) the role of mouse models in the research of thyroid cancer pathogenesis, and (ii) preclinical testing of potential anti-thyroid cancer therapeutics. The present review article aims to: (i) describe the current approaches for mouse modeling of thyroid cancer, (ii) provide insight into the biology and genetics of thyroid cancers, and (iii) offer guidance on the use of mouse models for testing potential therapeutics in preclinical settings. Based on research with mouse models of thyroid cancer pathogenesis involving the RTK, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, SRC, and JAK-STAT signaling pathways, inhibitors of VEGFR, MEK, mTOR, SRC, and STAT3 have been developed as anti-thyroid cancer drugs for "bench-to-bedside" translation. In the future, mouse models of thyroid cancer will be designed to be ''humanized" and "patient-like," offering opportunities to: (i) investigate the pathogenesis of thyroid cancer through target screening based on the CRISPR/Cas system, (ii) test drugs based on new mouse models, and (iii) explore the underlying mechanisms based on multi-omics.
Collapse
Affiliation(s)
- Yuchen Jin
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
| | - Min Liu
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China; Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China.
| | - Ri Sa
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
| | - Hao Fu
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
| | - Lin Cheng
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
| | - Libo Chen
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
| |
Collapse
|
|
16
|
Riley AS, McKenzie GAG, Green V, Schettino G, England RJA, Greenman J. The effect of radioiodine treatment on the diseased thyroid gland. Int J Radiat Biol 2019; 95:1718-1727. [DOI: 10.1080/09553002.2019.1665206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
| | - Gordon A. G. McKenzie
- Hull and East, Yorkshire Hospitals NHS Trust, Cottingham, UK
- Hull York Medical School, Hull, UK
| | | | - Giuseppe Schettino
- Medical Radiation Sciences Group, National Physical Laboratory, University of Surrey, Teddington, UK
| | | | | |
Collapse
|
|
17
|
Jezek J, Wang K, Yan R, Di Cristofano A, Cooper KF, Strich R. Synergistic repression of thyroid hyperplasia by cyclin C and Pten. J Cell Sci 2019; 132:jcs.230029. [PMID: 31331961 DOI: 10.1242/jcs.230029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 07/09/2019] [Indexed: 01/30/2023] Open
Abstract
The cyclin C-Cdk8 kinase has been identified as both a tumor suppressor and an oncogene depending on the cell type. The genomic locus encoding cyclin C (Ccnc) is often deleted in aggressive anaplastic thyroid tumors. To test for a potential tumor suppressor role for cyclin C, Ccnc alone, or Ccnc in combination with a previously described thyroid tumor suppressor Pten, was deleted late in thyroid development. Although mice harboring individual Pten or Ccnc deletions exhibited modest thyroid hyperplasia, the double mutant demonstrated dramatic thyroid expansion resulting in animal death by 22 weeks. Further analysis revealed that Ccncthyr-/- tissues exhibited a reduction in signal transducer and activator of transcription 3 (Stat3) phosphorylation at Ser727. Further analysis uncovered a post-transcriptional requirement of both Pten and cyclin C in maintaining the levels of the p21 and p53 tumor suppressors (also known as CDKN1A and TP53, respectively) in thyroid tissue. In conclusion, these data reveal the first tumor suppressor role for cyclin C in a solid tumor model. In addition, this study uncovers new synergistic activities of Pten and cyclin C to promote quiescence through maintenance of p21 and p53.
Collapse
Affiliation(s)
- Jan Jezek
- Department of Molecular Biology, Graduate School of Biological Sciences, Rowan University, Stratford, NJ 08084, USA
| | - Kun Wang
- Department of Molecular Biology, Graduate School of Biological Sciences, Rowan University, Stratford, NJ 08084, USA
| | - Ruilan Yan
- Department of Molecular Biology, Graduate School of Biological Sciences, Rowan University, Stratford, NJ 08084, USA
| | - Antonio Di Cristofano
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Katrina F Cooper
- Department of Molecular Biology, Graduate School of Biological Sciences, Rowan University, Stratford, NJ 08084, USA
| | - Randy Strich
- Department of Molecular Biology, Graduate School of Biological Sciences, Rowan University, Stratford, NJ 08084, USA
| |
Collapse
|
|
18
|
Wang N, Li Y, Wei J, Pu J, Liu R, Yang Q, Guan H, Shi B, Hou P, Ji M. TBX1 Functions as a Tumor Suppressor in Thyroid Cancer Through Inhibiting the Activities of the PI3K/AKT and MAPK/ERK Pathways. Thyroid 2019; 29:378-394. [PMID: 30543152 DOI: 10.1089/thy.2018.0312] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND TBX1 is a member of the T-box family of transcription factors characterized by a conserved DNA binding domain termed T-box. TBX1 has been reported to be downregulated in mouse skin tumors and is considered a negative regulator of tumor cell growth in mice. However, its role and exact mechanism in human cancers, including thyroid cancer, remain totally unknown. METHODS Quantitative reverse transcription polymerase chain reaction and Western blot assays were performed to evaluate the expression of investigated genes. Methylation-specific polymerase chain reaction and pyrosequencing were used to analyze TBX1 promoter methylation. The biological functions of TBX1 in thyroid cancer cells were determined by a series of in vitro and in vivo experiments. Chromatin immunoprecipitation sequencing and dual-luciferase reporter assays were used to identify its downstream targets. RESULTS This study demonstrates that TBX1 is frequently downregulated by promoter methylation in both papillary thyroid cancers and thyroid cancer cell lines. Ectopic expression of TBX1 in thyroid cancer cells dramatically inhibits cell viability, colony formation, and tumorigenic potential in nude mice, and induces cell-cycle arrest and apoptosis through modulating a panel of cell-cycle and apoptosis-related genes. In addition, ectopic expression of TBX1 significantly decreases the migration and invasion potential of thyroid cancer cells through inhibiting the process of epithelial-mesenchymal transition and the expression of matrix metalloproteinases. On the other hand, TBX1 knockdown markedly promotes thyroid cancer cell viability and invasiveness. Mechanistically, TBX1 exerts its tumor suppressor function in thyroid cancer cells through inhibiting phosphorylation of AKT at Ser473 and ERK via regulating its downstream targets such as RNF41, PARK2, and PHLPP2. CONCLUSIONS The data show that TBX1 is frequently inactivated by promoter methylation and functions as a potential tumor suppressor in thyroid cancer through inhibiting the activities of the PI3K/AKT and MAPK/ERK signaling pathways.
Collapse
Affiliation(s)
- Na Wang
- 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Yiqi Li
- 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Jing Wei
- 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Jun Pu
- 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Rui Liu
- 2 Department of Radio-Oncology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, P. R. China
| | - Qi Yang
- 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Haixia Guan
- 3 Department of Endocrinology and Metabolism, The First Affiliated Hospital of China Medical University, Shenyang, P.R. China
| | - Bingyin Shi
- 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
- 4 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, and The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Peng Hou
- 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
- 4 Key Laboratory for Tumor Precision Medicine of Shaanxi Province, and The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| | - Meiju Ji
- 5 Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China
| |
Collapse
|
|
19
|
Schweppe RE, Pozdeyev N, Pike LA, Korch C, Zhou Q, Sams SB, Sharma V, Pugazhenthi U, Raeburn C, Albuja-Cruz MB, Reigan P, LaBarbera DV, Landa I, Knauf JA, Fagin JA, Haugen BR. Establishment and Characterization of Four Novel Thyroid Cancer Cell Lines and PDX Models Expressing the RET/PTC1 Rearrangement, BRAFV600E, or RASQ61R as Drivers. Mol Cancer Res 2019; 17:1036-1048. [PMID: 30733375 DOI: 10.1158/1541-7786.mcr-18-1026] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/12/2018] [Accepted: 02/04/2019] [Indexed: 01/04/2023]
Abstract
Cancer cell lines are critical models to study tumor progression and response to therapy. In 2008, we showed that approximately 50% of thyroid cancer cell lines were redundant or not of thyroid cancer origin. We therefore generated new authenticated thyroid cancer cell lines and patient-derived xenograft (PDX) models using in vitro and feeder cell approaches, and characterized these models in vitro and in vivo. We developed four thyroid cancer cell lines, two derived from 2 different patients with papillary thyroid cancer (PTC) pleural effusions, CUTC5, and CUTC48; one derived from a patient with anaplastic thyroid cancer (ATC), CUTC60; and one derived from a patient with follicular thyroid cancer (FTC), CUTC61. One PDX model (CUTC60-PDX) was also developed. Short tandem repeat (STR) genotyping showed that each cell line and PDX is unique and match the original patient tissue. The CUTC5 and CUTC60 cells harbor the BRAF (V600E) mutation, the CUTC48 cell line expresses the RET/PTC1 rearrangement, and the CUTC61 cells have the HRAS (Q61R) mutation. Moderate to high levels of PAX8 and variable levels of NKX2-1 were detected in each cell line and PDX. The CUTC5 and CUTC60 cell lines form tumors in orthotopic and flank xenograft mouse models. IMPLICATIONS: We have developed the second RET/PTC1-expressing PTC-derived cell line in existence, which is a major advance in studying RET signaling. We have further linked all cell lines to the originating patients, providing a set of novel, authenticated thyroid cancer cell lines and PDX models to study advanced thyroid cancer.
Collapse
Affiliation(s)
- Rebecca E Schweppe
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado. .,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Nikita Pozdeyev
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Laura A Pike
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Christopher Korch
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.,Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Qiong Zhou
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Sharon B Sams
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.,Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Vibha Sharma
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Umarani Pugazhenthi
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Christopher Raeburn
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Maria B Albuja-Cruz
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Philip Reigan
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Daniel V LaBarbera
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Iñigo Landa
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Jeffrey A Knauf
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - James A Fagin
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Bryan R Haugen
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado.,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| |
Collapse
|
|
20
|
Zhang X, Sheng X, Miao T, Yao K, Yao D. Effect of insulin on thyroid cell proliferation, tumor cell migration, and potentially related mechanisms. Endocr Res 2019; 44:55-70. [PMID: 30260725 DOI: 10.1080/07435800.2018.1522641] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Diabetes has recently been identified as a risk factor for a variety of cancers, possibly due to hyperinsulinemia or exogenous insulin use. Thyroid cancer is the most common endocrine malignancy, and its incidence has been exponentially increasing worldwide at an alarming rate. The aim of this study was to establish whether insulin use affects thyroid cancer development and progression, specifically cell proliferation and migration in vitro. METHODS In this study, we investigated the effects of the insulin agents most commonly used in the clinic, regular human insulin (HI) and insulin glargine (IG), on the proliferation and migration of thyroid cells. RESULTS Both HI and IG affected the thyroid cells in a dose-dependent manner and at high concentrations significantly promoted thyroid cell proliferation and tumor cell migration. The promoting effect might be elicited by activation of the insulin receptor and insulin-like growth factor-1 receptor and through the downstream Akt-signaling pathway, which inhibits the activity of the tumor-suppressor FoxO3a. In particular, MAPK-signaling cascades were activated in papillary thyroid carcinoma cell-1 cells but not in follicular rat thyroid-5 cells. CONCLUSION The in vitro evidence demonstrated that HI and IG can promote thyroid cell proliferation and tumor cell migration at supraphysiological concentrations, but the effect was not significant at low concentrations. Whether high-dose insulins could affect diabetic patients with thyroid cancer or undetected (pre)cancerous lesions needs further in vivo study. ABBREVIATIONS HI: human regular insulin; IG: insulin glargine; IR: insulin receptor; IGF-1R: insulin-like growth factor-1 receptor; Akt: protein kinase B (PKB); MAPK: mitogen-activated protein kinase; FoxO3a: the forkhead box-containing protein: class O 3a.
Collapse
Affiliation(s)
- Xinxia Zhang
- a Department of Geriatrics , The First Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou , Zhejiang , China
| | - Xiaoli Sheng
- b Department of Obstetrics , The First Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou , Zhejiang , China
| | - Tingru Miao
- c ECG Functional Department , Zhejiang Province People's Hospital , Hangzhou , Zhejiang , China
| | - Kannan Yao
- d The Second Central Laboratory , The First Affiliated Hospital of Zhejiang Chinese Medical University , Hangzhou , Zhejiang , China
| | - Dingguo Yao
- e Department of Endocrinology , The First Affiliated Hospital of Zhejiang Chinese Medical University , Hangzhou , Zhejiang , China
| |
Collapse
|
|
21
|
Du Z, Wang Q, Ma G, Jiao J, Jiang D, Zheng X, Qiu M, Liu S. Inhibition of Nrf2 promotes the antitumor effect of Pinelliae rhizome in papillary thyroid cancer. J Cell Physiol 2019; 234:13867-13877. [PMID: 30697724 DOI: 10.1002/jcp.28069] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 12/18/2018] [Indexed: 12/30/2022]
Abstract
We previously reported that Xiaotan Sanjie (XTSJ) decoction can prevent the progression of gastric cancer in vitro and in vivo. Pinelliae rhizome (PR), one component of XTSJ decoction, has an inhibitory effect on the growth and proliferation of tumor cells. The present study investigated the underlying mechanisms of action of PR. Using the human papillary thyroid cancer cell lines, TPC-1 and BCPAP, we found that XTSJ decoction and PR alone decreased cell viability to a similar extent in both cell lines, whereas treatment with XTJS decoction without PR [PR (-)] had a lesser effect. PR treatment inhibited the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in a dose-dependent manner. To investigate the role of Nrf2 in the PR-mediated effects of XTSJ, knockdown of Nrf2 in the tumor cell lines using Nrf2 siRNA (siNrf2) was performed and transfected cells were treated with PR. Silencing of Nrf2 amplified the effects on autophagy, cell viability, apoptosis, and colony formation. Similar results were obtained following treatment with the autophagy inhibitor 3-methyladenine (3-MA). Furthermore, treatment with PR, siNrf2, and/or 3-MA inhibited the MAPK pathway, and analysis of the MAPK pathway components confirmed the role of this pathway in the PR-mediated cellular effects. In mice implanted with siNrf2-transfected cells, the effects of PR were amplified. Taken together, these findings indicate that PR is critical for the inhibitory effects of XTSJ decoction on tumor cell viability and that downregulation of Nrf2 promotes the antitumor effects of PR on papillary thyroid cancer cells.
Collapse
Affiliation(s)
- Zhipeng Du
- Department of General Surgery III, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qiang Wang
- Department of General Surgery III, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Guanjun Ma
- Department of General Surgery III, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jianpeng Jiao
- Department of Traditional Chinese Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Daozhen Jiang
- Department of General Surgery III, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiangmin Zheng
- Department of General Surgery III, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ming Qiu
- Department of General Surgery III, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Sheng Liu
- Department of General Surgery III, Changzheng Hospital, Second Military Medical University, Shanghai, China
| |
Collapse
|
|
22
|
Saini S, Tulla K, Maker AV, Burman KD, Prabhakar BS. Therapeutic advances in anaplastic thyroid cancer: a current perspective. Mol Cancer 2018; 17:154. [PMID: 30352606 PMCID: PMC6198524 DOI: 10.1186/s12943-018-0903-0] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/08/2018] [Indexed: 02/08/2023] Open
Abstract
Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success.
Collapse
Affiliation(s)
- Shikha Saini
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL USA
| | - Kiara Tulla
- Department of Surgery, Division of Surgical Oncology, University of Illinois-College of Medicine, Chicago, IL USA
| | - Ajay V. Maker
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL USA
- Department of Surgery, Division of Surgical Oncology, University of Illinois-College of Medicine, Chicago, IL USA
| | | | - Bellur S. Prabhakar
- Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL USA
- Jesse Brown VA Medical Center, Chicago, IL USA
| |
Collapse
|
|
23
|
Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. Oncotarget 2018; 8:24604-24620. [PMID: 28445948 PMCID: PMC5421873 DOI: 10.18632/oncotarget.15599] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 02/06/2017] [Indexed: 12/17/2022] Open
Abstract
Anaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3′-kinase inhibitor in pre-clinical models. We used human thyroid cancer cell lines and genetically engineered double mutant BRAFV600E PIK3CAH1047R mice to evaluate the effect of both inhibitors separately or in combination in terms of proliferation and signaling in vitro; tumor burden, histology, cell death induction and tumor markers expression in vivo. The combination of MEK and Pi’3-kinase inhibition shows a synergistic effect in term of proliferation and apoptosis induction through Survivin down-regulation in vitro. We show for the first time the effects of the combination of a MEK inhibitor and Pi3′-kinase inhibitor in a genetically engineered mouse model of aggressively lethal thyroid cancer. In fine, the two drugs cooperate to promote tumor shrinkage by inducing a proliferation arrest and an elevation of apoptosis in vivo. Moreover, a phenotypic reversion is also observed with a partial restoration of normal thyroid marker transcription, and thyroid cancer marker expression reduction. In conclusion, combination therapy of MEK and Pi3′-kinase inhibition synergizes to target double mutant thyroid cancer in vitro and in vivo. This multidrug approach could readily be translated into clinical practice and bring new perspectives for the treatment of incurable thyroid carcinoma.
Collapse
|
|
24
|
CRLF1 promotes malignant phenotypes of papillary thyroid carcinoma by activating the MAPK/ERK and PI3K/AKT pathways. Cell Death Dis 2018. [PMID: 29515111 PMCID: PMC5841418 DOI: 10.1038/s41419-018-0352-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Papillary thyroid carcinoma (PTC) is the one of the most common types of endocrine cancer and has a heterogeneous prognosis. Tumors from patients with poor prognosis may differentially express specific genes. Therefore, an analysis of The Cancer Genome Atlas (TCGA) database was performed and revealed that cytokine receptor-like factor 1 (CRLF1) may be a potential novel target for PTC treatment. The objective of the current study was to explore the expression of CRLF1 in PTC and to investigate the main functions and mechanisms of CRLF1 in PTC. PTC tissues exhibited higher CRLF1 expression at both the mRNA and protein levels than it did with normal thyroid tissues. High CRLF1 levels were associated with aggressive clinicopathological features and poor disease-free survival rates. By using loss-of-function and gain-of-function assays, we found that CRLF1 not only increased cell migration and invasion in vitro but also promoted tumor growth both in vitro and in vivo. In addition, CRLF1 induced epithelial–mesenchymal transitions. Overexpression of CRLF1 activated the ERK1/2 and AKT pathways. The oncogenic effects induced by CRLF1 were suppressed by treating the cells with the MEK inhibitor U0126 or the AKT inhibitor MK-2206. These results suggest that CRLF1 enhances cell proliferation and metastasis in PTC and thus may therefore be a potential therapeutic target for PTC.
Collapse
|
|
25
|
Beadnell TC, Nassar KW, Rose MM, Clark EG, Danysh BP, Hofmann MC, Pozdeyev N, Schweppe RE. Src-mediated regulation of the PI3K pathway in advanced papillary and anaplastic thyroid cancer. Oncogenesis 2018; 7:23. [PMID: 29487290 PMCID: PMC5833015 DOI: 10.1038/s41389-017-0015-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 11/06/2017] [Accepted: 11/22/2017] [Indexed: 02/07/2023] Open
Abstract
Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients. To address this issue, we have focused on targeting the non-receptor tyrosine kinase, Src, and we and others have demonstrated that targeting Src results in inhibition of growth, invasion, and migration both in vitro and in vivo, which can be enhanced through the combined inhibition of Src and the MAPK pathway. Therefore, we examined the efficacy of the combination therapy across a panel of thyroid cancer cell lines representing common oncogenic drivers (BRAF, RAS, and PIK3CA). Interestingly, combined inhibition of Src and the MAPK pathway overcomes intrinsic dasatinib resistance in cell lines where both the MAPK and PI3K pathways are inhibited, which we show is likely due to the regulation of the PI3K pathway by Src in these responsive cells. Interestingly, we have mapped downstream phosphorylation of rpS6 as a key biomarker of response, and cells that maintain rpS6 phosphorylation likely represent drug tolerant persisters. Altogether, the combined inhibition of Src and the MAPK pathway holds great promise for improving the overall survival of advanced thyroid cancer patients with BRAF and RAS mutations, and activation of the PI3K pathway and rpS6 phosphorylation represent important biomarkers of response for patients treated with this therapy.
Collapse
Affiliation(s)
- Thomas C Beadnell
- Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Kelsey W Nassar
- Medical Oncology, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Madison M Rose
- Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Erin G Clark
- Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Brian P Danysh
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marie-Claude Hofmann
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nikita Pozdeyev
- Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Rebecca E Schweppe
- Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
| |
Collapse
|
|
26
|
Long-term vemurafenib treatment drives inhibitor resistance through a spontaneous KRAS G12D mutation in a BRAF V600E papillary thyroid carcinoma model. Oncotarget 2017; 7:30907-23. [PMID: 27127178 PMCID: PMC5058727 DOI: 10.18632/oncotarget.9023] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 03/31/2016] [Indexed: 01/04/2023] Open
Abstract
The BRAF V600E mutation is commonly observed in papillary thyroid cancer (PTC) and predominantly activates the MAPK pathway. Presence of BRAF V600E predicts increasing risk of recurrence and higher mortality rate, and treatment options for such patients are limited. Vemurafenib, a BRAF V600E inhibitor, is initially effective, but cells inevitably develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in short-term cultures of PTC cells; however, mechanisms of acquired resistance have not. In the present study, we investigated possible adaptive mechanisms of BRAF V600E inhibitor resistance in KTC1 thyroid cancer cells following long-term vemurafenib exposure. We found that a subpopulation of KTC1 cells acquired resistance to vemurafenib following 5 months of treatment with the inhibitor. Resistance coincided with the spontaneous acquisition of a KRAS G12D activating mutation. Increases in activated AKT, ERK1/2, and EGFR were observed in these cells. In addition, the resistant cells were less sensitive to combinations of vemurafenib and MEK1 inhibitor or AKT inhibitor. These results support the KRAS G12D mutation as a genetic mechanism of spontaneously acquired secondary BRAF inhibitor resistance in BRAF V600E thyroid cancer cells.
Collapse
|
|
27
|
Denaro M, Ugolini C, Poma AM, Borrelli N, Materazzi G, Piaggi P, Chiarugi M, Miccoli P, Vitti P, Basolo F. Differences in miRNA expression profiles between wild-type and mutated NIFTPs. Endocr Relat Cancer 2017; 24:543-553. [PMID: 28830935 DOI: 10.1530/erc-17-0167] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 07/27/2017] [Indexed: 12/18/2022]
Abstract
Noninvasive encapsulated follicular variants of papillary thyroid carcinomas have been recently reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). NIFTPs exhibit a behavior that is very close to that of follicular adenomas but different from the infiltrative and invasive follicular variants of papillary thyroid carcinomas (FVPTCs). The importance of miRNAs to carcinogenesis has been reported in recent years. miRNAs seem to be promising diagnostic and prognostic molecular markers for thyroid cancer, and the combination of miRNA expression and mutational status might improve cytological diagnosis. The aim of the present study was to evaluate the miRNA expression profile in wild-type, RAS- or BRAF-mutated NIFTPs, infiltrative and invasive FVPTCs, and follicular adenomas using the nCounter miRNA Expression assay (NanoString Technologies). To identify the significant Kyoto Encyclopedia of Genes and Genomes (KEGG) molecular pathways associated with deregulated miRNAs, we used the union of pathways option in DNA Intelligent Analysis (DIANA) miRPath software. We have shown that the miRNA expression profiles of wild-type and mutated NIFTPs could be different. The expression profile of wild-type NIFTPs seems comparable to that of follicular adenomas, whereas mutated NIFTPs have an expression profile similar to that of infiltrative and invasive FVPTCs. The upregulation of 4 miRNAs (miR-221-5p, miR-221-3p, miR-222-3p, miR-146b-5p) and the downregulation of 8 miRNAs (miR-181a-3p, miR-28-5p, miR-363-3p, miR-342-3p, miR-1285-5p, miR-152-3p, miR-25-3p, miR-30e-3) in mutated NIFTPs compared to wild-type ones suggest a potential invasive-like phenotype by deregulating the specific pathways involved in cell adhesion and cell migration (Hippo signaling pathway, ECM-receptor interaction, adherens junction, regulation of actin cytoskeleton, fatty acid biosynthesis and metabolism).
Collapse
Affiliation(s)
- Maria Denaro
- Department of Surgical PathologyMedical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Clara Ugolini
- Department of Laboratory MedicineSection of Pathology Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Anello Marcello Poma
- Department of Surgical PathologyMedical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Nicla Borrelli
- Department of Surgical PathologyMedical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Gabriele Materazzi
- Department of Surgical PathologyMedical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Paolo Piaggi
- National Institute of Diabetes and Digestive and Kidney DiseasesPhoenix, Arizona, USA
| | - Massimo Chiarugi
- Department of Surgical PathologyMedical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Paolo Miccoli
- Department of Surgical PathologyMedical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| | - Paolo Vitti
- Department of Clinical and Experimental MedicineUniversity of Pisa, Pisa, Italy
| | - Fulvio Basolo
- Department of Surgical PathologyMedical, Molecular and Critical Area, University of Pisa, Pisa, Italy
| |
Collapse
|
|
28
|
Yin DT, Lei M, Xu J, Li H, Wang Y, Liu Z, Ma R, Yu K, Li X. The Chinese herb Prunella vulgaris promotes apoptosis in human well-differentiated thyroid carcinoma cells via the B-cell lymphoma-2/Bcl-2-associated X protein/caspase-3 signaling pathway. Oncol Lett 2017; 14:1309-1314. [PMID: 28808482 PMCID: PMC5542033 DOI: 10.3892/ol.2017.6317] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 02/07/2017] [Indexed: 01/20/2023] Open
Abstract
Prunella vulgaris (PV), a traditional Chinese herb, has been shown to be rich in bioactive chemicals and possess anti-proliferative and pro-apoptotic effects on tumor cells. The effect of PV on human well-differentiated thyroid carcinoma (WDTC), which accounts for the majority of common endocrine malignancies, remains to be elucidated. The present study aimed to investigate the function of PV on WDTC cell lines and apoptosis-associated signaling pathway activity. Additional studies demonstrated that PV may induce apoptosis in WDTC TPC-1 and FTC-133 cell lines, using the Cell Counting Kit-8 assay. Morphological changes of apoptotic cells were observed by Hoechst 33342 and acridine orange/ethidium bromide staining. In addition, ladder pattern of fragmented DNA was observed by DNA gel electrophoresis. It was also observed that PV significantly increased Bcl-2-associated X protein and caspase-3 expression, and downregulated B-cell lymphoma-2 expression in TPC-1 and FTC-133 by reverse transcription-quantitative polymerase chain reaction (P<0.05). Thus, the present results indicated that PV has the potential to be a future WDTC therapeutic agent.
Collapse
Affiliation(s)
- De-Tao Yin
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Mengyuan Lei
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Jianhui Xu
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Hongqiang Li
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Yongfei Wang
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Zhen Liu
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Runsheng Ma
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Kun Yu
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| | - Xianghua Li
- Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Key Discipline Laboratory of Clinical Medicine Henan, Zhengzhou, Henan 450050, P.R. China
| |
Collapse
|
|
29
|
Gunda V, Sarosiek KA, Brauner E, Kim YS, Amin S, Zhou Z, Letai A, Parangi S. Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis. Cancer Lett 2017; 395:1-10. [DOI: 10.1016/j.canlet.2017.02.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 02/21/2017] [Accepted: 02/22/2017] [Indexed: 10/20/2022]
|
|
30
|
Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. Oncotarget 2017. [PMID: 28445948 DOI: 10.18632/oncotarget.15599.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Anaplastic thyroid cancers and radioiodine resistant thyroid cancer are posing a major treat since surgery combined with Iodine131 therapy is ineffective on them. Small-molecule inhibitors are presenting a new hope for patients, but often lead to drug resistance in many cancers. Based on the major mutations found in thyroid cancer, we propose the combination of a MEK inhibitor and a Pi3'-kinase inhibitor in pre-clinical models. We used human thyroid cancer cell lines and genetically engineered double mutant BRAFV600E PIK3CAH1047R mice to evaluate the effect of both inhibitors separately or in combination in terms of proliferation and signaling in vitro; tumor burden, histology, cell death induction and tumor markers expression in vivo. The combination of MEK and Pi'3-kinase inhibition shows a synergistic effect in term of proliferation and apoptosis induction through Survivin down-regulation in vitro. We show for the first time the effects of the combination of a MEK inhibitor and Pi3'-kinase inhibitor in a genetically engineered mouse model of aggressively lethal thyroid cancer. In fine, the two drugs cooperate to promote tumor shrinkage by inducing a proliferation arrest and an elevation of apoptosis in vivo. Moreover, a phenotypic reversion is also observed with a partial restoration of normal thyroid marker transcription, and thyroid cancer marker expression reduction.In conclusion, combination therapy of MEK and Pi3'-kinase inhibition synergizes to target double mutant thyroid cancer in vitro and in vivo. This multidrug approach could readily be translated into clinical practice and bring new perspectives for the treatment of incurable thyroid carcinoma.
Collapse
|
|
31
|
Liang W, Lai Y, Zhu M, Huang S, Feng W, Gu X. Combretastatin A4 Regulates Proliferation, Migration, Invasion, and Apoptosis of Thyroid Cancer Cells via PI3K/Akt Signaling Pathway. Med Sci Monit 2016; 22:4911-4917. [PMID: 27966519 PMCID: PMC5179240 DOI: 10.12659/msm.898545] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background Combretastatin A4 (CA4) is a potential therapeutic candidate for a variety of human cancer treatments. However, the inhibitive effects of CA4 on thyroid cancer cells are still not well-clarified. This study aimed to investigate the potential effect of CA4 on thyroid cancer cells, as well as underlying mechanism. Material/Methods Human thyroid papillary carcinoma cell line TPC1 was pre-treated with 5 concentrations of CA4 (0, 1, 2, 5, or 10 μM) for 2 h. Cell proliferation was determined by 3-(4, 5-dimethyl-2- thiazolyl)-2, 5-diphenyl -2-H-tetrazolium bromide (MTT) assay. Cell migration and invasion were detected by a modified Boyden chamber assay. Moreover, cell apoptosis was detected by terminal deoxynucleotidyl (TUNEL) staining assay and flow cytometry method. Western blot analysis was performed to determine the expression changes of epithelial-mesenchymal transition (EMT)-related proteins and phosphatidylinositol-3-kinase/serine/threonine kinase (PI3K/Akt) signaling pathway proteins. Results CA4 significantly inhibited the cell proliferation, migration, and invasion, and significantly promoted cell apoptosis in a dose-dependent manner compared with the control group. The EMT-related protein levels of N-Cadherin, Vimentin, Snail1, Slug, Twist1, and ZEB1 were significantly decreased by CA4, while E-cadherin had no significant difference compared with the control group. Moreover, PI3K/Akt signaling pathway protein levels of p-PI3K and p-Akt were significantly decreased, whereas PI3K and Akt had no significant differences compared with the control group. Conclusions CA4 can inhibit proliferation, migration, and invasion and promote apoptosis of TPC1 cells. These effects might be through the PI3K/Akt signaling pathway. CA4 may be a potential therapeutic target for the treatment of thyroid cancer.
Collapse
Affiliation(s)
- Weixin Liang
- Department of General Surgery, Affiliated Gaoming Hospital of Guangdong Medical University, Foshan, Guangdong, China (mainland)
| | - Yongqiang Lai
- Department of General Surgery, Affiliated Gaoming Hospital of Guangdong Medical University, Foshan, Guangdong, China (mainland)
| | - Mingzhang Zhu
- Department of General Surgery, Affiliated Gaoming Hospital of Guangdong Medical University, Foshan, Guangdong, China (mainland)
| | - Shangshu Huang
- Department of General Surgery, Affiliated Gaoming Hospital of Guangdong Medical University, Foshan, Guangdong, China (mainland)
| | - Weizhao Feng
- Department of General Surgery, Affiliated Gaoming Hospital of Guangdong Medical University, Foshan, Guangdong, China (mainland)
| | - Xiaoyu Gu
- Department of General Surgery, Affiliated Gaoming Hospital of Guangdong Medical University, Foshan, Guangdong, China (mainland)
| |
Collapse
|
|
32
|
Nozhat Z, Hedayati M. PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas. Mol Diagn Ther 2016; 20:13-26. [PMID: 26597586 DOI: 10.1007/s40291-015-0175-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Thyroid malignancies are the most common endocrine system carcinomas, with four histopathological forms. The phosphoinositide 3-kinase-protein kinase B/AKT (PI3K-PKB/AKT) pathway is one of the most critical molecular signaling pathways implicated in key cellular processes. Its continuous activation by several aberrant receptor tyrosine kinases (RTKs) and genetic mutations in its downstream effectors result in high cell proliferation in a broad number of cancers, including thyroid carcinomas. In this review article, the role of different signaling pathways of PI3K/AKT in thyroid cancers, with the emphasis on the PI3K/AKT/mammalian target of rapamycin (mTOR), PI3K/AKT/forkhead box O (FOXO) and PI3K/AKT/phosphatase and tensin homolog deleted on chromosome ten (PTEN) pathways, and various therapeutic strategies targeting these pathways have been summarized. In most of the in vitro studies, agents inhibiting mTOR in monotherapy or in combination with chemotherapy for thyroid malignancies have been introduced as promising anticancer therapies. FOXOs and PTEN are two outstanding downstream targets of the PI3K/AKT pathway. At the present time, no study has been undertaken to consider thyroid cancer treatment via FOXOs and PTEN targeting. According to the critical role of these proteins in cell cycle arrest, it seems that a treatment strategy based on the combination of FOXOs or PTEN activity induction with PI3K/AKT downstream mediators (e.g., mTOR) inhibition will be beneficial and promising in thyroid cancer treatment.
Collapse
Affiliation(s)
- Zahra Nozhat
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Biotechnology Department, School of Advanced Technology in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
33
|
Nucera C. Evolution of resistance to thyroid cancer therapy. Aging (Albany NY) 2016; 8:1576-7. [PMID: 27575377 PMCID: PMC5032682 DOI: 10.18632/aging.101030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 08/27/2016] [Indexed: 11/25/2022]
Affiliation(s)
- Carmelo Nucera
- Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Experimental Pathology, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| |
Collapse
|
|
34
|
Wang FY, Wang XM, Wang C, Wang XF, Zhang YQ, Wu JD, Wu F, Zhang WJ, Zhang L. Suppression of Mcl-1 induces apoptosis in mouse peritoneal macrophages infected withMycobacterium tuberculosis. Microbiol Immunol 2016; 60:215-27. [DOI: 10.1111/1348-0421.12368] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 02/03/2016] [Accepted: 02/08/2016] [Indexed: 02/03/2023]
Affiliation(s)
- Fei-yu Wang
- Medical College of Shihezi University
- Department of Pathophysiology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Xin-min Wang
- Medical College of Shihezi University
- Department of Urinary Surgery; First Affiliated Hospital
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Chan Wang
- Medical College of Shihezi University
- Department of Pathogen Biology and Immunology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Xiao-fang Wang
- Medical College of Shihezi University
- Department of Pathophysiology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Yu-qing Zhang
- Medical College of Shihezi University
- Department of Pathophysiology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Jiang-dong Wu
- Medical College of Shihezi University
- Department of Pathophysiology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Fang Wu
- Medical College of Shihezi University
- Department of Pathophysiology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Wan-jiang Zhang
- Medical College of Shihezi University
- Department of Pathophysiology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| | - Le Zhang
- Medical College of Shihezi University
- Department of Pathophysiology
- Key Laboratory of Xinjiang Endemic and Ethnic Diseases in cooperation with the Education Ministry of Xinjiang Province; Xinjiang; Shihezi China
| |
Collapse
|
|
35
|
Role of p38 MAPK activation and mitochondrial cytochrome-c release in allicin-induced apoptosis in SK-N-SH cells. Anticancer Drugs 2016; 27:312-7. [DOI: 10.1097/cad.0000000000000340] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
36
|
Riahi-Chebbi I, Haoues M, Essafi M, Zakraoui O, Fattouch S, Karoui H, Essafi-Benkhadir K. Quince peel polyphenolic extract blocks human colon adenocarcinoma LS174 cell growth and potentiates 5-fluorouracil efficacy. Cancer Cell Int 2016; 16:1. [PMID: 26839513 PMCID: PMC4736700 DOI: 10.1186/s12935-016-0276-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Accepted: 01/26/2016] [Indexed: 01/01/2023] Open
Abstract
Background Development of alternative cancer-specific drugs would be of paramount importance to overcome toxicity toward normal tissues and tumor resistance. Here, we investigated the potential anti-tumoral effect of peel (Peph) and pulp polyphenolic extracts from the Tunisian quince Cydonia oblonga Miller on both no-tumorigenic cells NIH 3T3 Fibroblasts and HEK 293 cells and human colon adenocarcinoma LS174 cells. Methods Cell proliferation and cytotoxicity were measured with MTT and LDH assays respectively. Cell cycle distribution and the apoptosis levels were assessed by flow cytometry. Intracellular reactive oxygen species (ROS) levels were determined using the fluorescent probe CM-H2DCFDA. Western blot was used to further characterize cell death and analyze the signaling pathways affected by Peph treatment. The expression level of VEGF-A was evaluated by real time quantitative PCR and further verified by quantifying the secreted cytokines by enzyme-linked immunosorbent assay. Results We found that Peph extract displayed the highest anti-proliferative effect specifically on LS174 cells. However, each Peph phenolic compound alone did not exhibit any anti-proliferative activity, suggesting a synergistic effect of phenolic molecules. Such effect was associated with a cell cycle arrest in the G1/S phase, a caspase-independent apoptosis and an increase of the ROS production. Peph extract inhibited the pro-survival signaling pathway NFκB and suppressed the expression of various cellular markers known to be involved in cell cycling (cyclin D1) and angiogenesis (Vascular Endothelial Growth Factor, VEGF). Interestingly, the combination Peph extract and 5-FU exerted synergistic inhibitory effect on cell viability. Conclusion These data propose the quince Peph extract as a promising cost effective non toxic drug to employ alone or in combination with conventional anti-colorectal cancer. Moreover, quince rich regimen may prevent the development and the progress of colon cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12935-016-0276-7) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Ichrak Riahi-Chebbi
- Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 13 Place Pasteur, BP 74, 1002 Tunis-Belvédère, Tunisia ; Université de Tunis El Manar, 1068 Tunis, Tunisia
| | - Meriam Haoues
- Laboratoire de Recherche sur la Transmission, le Contrôle et l'Immunobiologie des Infections (LR11IPT02), Institut Pasteur de Tunis, 1002 Tunis, Tunisia ; Université de Tunis El Manar, 1068 Tunis, Tunisia
| | - Makram Essafi
- Laboratoire de Recherche sur la Transmission, le Contrôle et l'Immunobiologie des Infections (LR11IPT02), Institut Pasteur de Tunis, 1002 Tunis, Tunisia ; Université de Tunis El Manar, 1068 Tunis, Tunisia
| | - Ons Zakraoui
- Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 13 Place Pasteur, BP 74, 1002 Tunis-Belvédère, Tunisia ; Université de Tunis El Manar, 1068 Tunis, Tunisia
| | - Sami Fattouch
- Institut National des Sciences Appliquées et de Technologie (INSAT), Université de Carthage, Tunis, Tunisia
| | - Habib Karoui
- Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 13 Place Pasteur, BP 74, 1002 Tunis-Belvédère, Tunisia ; Université de Tunis El Manar, 1068 Tunis, Tunisia
| | - Khadija Essafi-Benkhadir
- Laboratoire d'Epidémiologie Moléculaire et de Pathologie Expérimentale Appliquée Aux Maladies Infectieuses (LR11IPT04), Institut Pasteur de Tunis, 13 Place Pasteur, BP 74, 1002 Tunis-Belvédère, Tunisia ; Université de Tunis El Manar, 1068 Tunis, Tunisia
| |
Collapse
|
|
37
|
Zhang K, He X, Zhou Y, Gao L, Qi Z, Chen J, Gao X. Atorvastatin Ameliorates Radiation-Induced Cardiac Fibrosis in Rats. Radiat Res 2015; 184:611-20. [DOI: 10.1667/rr14075.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
|
|
38
|
Yang M, Du L, Li W, Shen F, Fan Z, Jian Z, Hou R, Shen Y, Yue B, Zhang X. Profile of microRNA in Giant Panda Blood: A Resource for Immune-Related and Novel microRNAs. PLoS One 2015; 10:e0143242. [PMID: 26599861 PMCID: PMC4658108 DOI: 10.1371/journal.pone.0143242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 11/01/2015] [Indexed: 11/18/2022] Open
Abstract
The giant panda (Ailuropoda melanoleuca) is one of the world's most beloved endangered mammals. Although the draft genome of this species had been assembled, little was known about the composition of its microRNAs (miRNAs) or their functional profiles. Recent studies demonstrated that changes in the expression of miRNAs are associated with immunity. In this study, miRNAs were extracted from the blood of four healthy giant pandas and sequenced by Illumina next generation sequencing technology. As determined by miRNA screening, a total of 276 conserved miRNAs and 51 novel putative miRNAs candidates were detected. After differential expression analysis, we noticed that the expressions of 7 miRNAs were significantly up-regulated in young giant pandas compared with that of adults. Moreover, 2 miRNAs were up-regulated in female giant pandas and 1 in the male individuals. Target gene prediction suggested that the miRNAs of giant panda might be relevant to the expressions of 4,602 downstream genes. Subseuqently, the predicted target genes were conducted to KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and we found that these genes were mainly involved in host immunity, including the Ras signaling pathway, the PI3K-Akt signaling pathway, and the MAPK signaling pathway. In conclusion, our results provide the first miRNA profiles of giant panda blood, and the predicted functional analyses may open an avenue for further study of giant panda immunity.
Collapse
Affiliation(s)
- Mingyu Yang
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, 610064, P.R. China
| | - Lianming Du
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, 610064, P.R. China
| | - Wujiao Li
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, 610064, P.R. China
| | - Fujun Shen
- The Key Laboratory for Conservation Biology of Endangered Wildlife, Sichuan Province, Chengdu Research Base of Giant Panda Breeding, Chengdu, Sichuan, 610081, China
| | - Zhenxin Fan
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, 610064, P.R. China
| | - Zuoyi Jian
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, 610064, P.R. China
| | - Rong Hou
- The Key Laboratory for Conservation Biology of Endangered Wildlife, Sichuan Province, Chengdu Research Base of Giant Panda Breeding, Chengdu, Sichuan, 610081, China
| | - Yongmei Shen
- Gooddoctor pharmaceutical Group, NO.88 Yingkou Road, Chengdu, Sichuan, 610000, China
| | - Bisong Yue
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, 610064, P.R. China
| | - Xiuyue Zhang
- Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, 610064, P.R. China
| |
Collapse
|
|
39
|
Characterization of thyroid cancer cell lines in murine orthotopic and intracardiac metastasis models. Discov Oncol 2015; 6:87-99. [PMID: 25800363 DOI: 10.1007/s12672-015-0219-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 02/27/2015] [Indexed: 01/29/2023] Open
Abstract
Thyroid cancer incidence has been increasing over time, and it is estimated that ∼1950 advanced thyroid cancer patients will die of their disease in 2015. To combat this disease, an enhanced understanding of thyroid cancer development and progression as well as the development of efficacious, targeted therapies are needed. In vitro and in vivo studies utilizing thyroid cancer cell lines and animal models are critically important to these research efforts. In this report, we detail our studies with a panel of authenticated human anaplastic and papillary thyroid cancer (ATC and PTC) cell lines engineered to express firefly luciferase in two in vivo murine cancer models-an orthotopic thyroid cancer model as well as an intracardiac injection metastasis model. In these models, primary tumor growth in the orthotopic model and the establishment and growth of metastases in the intracardiac injection model are followed in vivo using an IVIS imaging system. In the orthotopic model, the ATC cell lines 8505C and T238 and the PTC cell lines K1/GLAG-66 and BCPAP had take rates >90 % with final tumor volumes ranging 84-214 mm(3) over 4-5 weeks. In the intracardiac model, metastasis establishment was successful in the ATC cell lines HTh74, HTh7, 8505C, THJ-16T, and Cal62 with take rates ≥70 %. Only one of the PTC cell lines tested (BCPAP) was successful in the intracardiac model with a take rate of 30 %. These data will be beneficial to inform the choice of cell line and model system for the design of future thyroid cancer studies.
Collapse
|
|
40
|
Xu H, Li X, Ding W, Zeng X, Kong H, Wang H, Xie W. Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway. Cancer Cell Int 2015; 15:25. [PMID: 25741219 PMCID: PMC4349657 DOI: 10.1186/s12935-015-0166-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 01/20/2015] [Indexed: 12/31/2022] Open
Abstract
Background Duguelin is a rotenoid extracted from plants and has potent antitumor effects in vitro and in vivo. However, the mechanism underlying the antitumor effect remains unclear. Our preliminary study showed that Deguelin is effective to stimulate the generation of Reactive Oxygen Species (ROS). In the current study, we evaluated the in vitro cytotoxicity of Deguelin against lung cancer cells and studied whether a ROS scavenger, N-acetyl-cysteine (NAC), can reverse the inhibitory effect of Deguelin. Results We showed that the dose-dependent apoptotic inducing effect of Deguelin could be partially reversed by the co-administration of NAC. Moreover, Deguelin reduced the phosphorylation of Akt protein and induced the apoptotic protein Caspase-3 in a dose-dependent manner. Co-treatment with NAC partially attenuated this effect and rescued some cells from apoptosis. Conclusion Deguelin induces the apoptosis of cancer cells through a ROS driven Akt pathway, which could translate into a promising therapeutic for lung cancer.
Collapse
Affiliation(s)
- Huae Xu
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China ; Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, 210029 People's Republic of China
| | - Xiaolin Li
- Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Wenqiu Ding
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, 210029 People's Republic of China
| | - Xiaoning Zeng
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, 210029 People's Republic of China
| | - Hui Kong
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, 210029 People's Republic of China
| | - Hong Wang
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, 210029 People's Republic of China
| | - Weiping Xie
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, 210029 People's Republic of China
| |
Collapse
|
|
41
|
Ma W, Zhang D, Zheng L, Zhan Y, Zhang Y. Potential roles of Centipede Scolopendra extracts as a strategy against EGFR-dependent cancers. Am J Transl Res 2015; 7:39-52. [PMID: 25755827 PMCID: PMC4346522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 11/25/2014] [Indexed: 06/04/2023]
Abstract
Centipede Scolopendra, a commonly used traditional Chinese medicine, has been shown to have anti-cancer effects. In this study, the inhibitory effect of alcohol extracts of Centipede Scolopendra (AECS) was more prominent when treating cells highly expressing epidermal growth factor receptor (EGFR) (A431 and HEK293/EGFR cells versus HEK293 cells). The elution profiles of AECS on cell membrane chromatography (CMC) column showed that AECS could bind to EGFR, and competition studies indicated that AECS and gefitinib may have direct competition at a single common binding site on EGFR. SiRNA knockdown of EGFR in A431 cells attenuated AECS effects, suggesting that EGFR was a target mediated by AECS. In a cell culture system, AECS dramatically induced apoptosis of A431 and HEK293/EGFR cells, which was associated with the effects on Bcl-2 family. Furthermore, AECS could alter EGFR kinase activity and reduce phosphorylation of EGFR and downstream signaling players AKT and Erk1/2. The mechanism of AECS to inhibit high-EGFR expression cell proliferation is due to its ability to induce apoptosis and modulate the EGFR pathway. This study might provide a novel therapy for cancer with high-EGFR expression.
Collapse
Affiliation(s)
- Weina Ma
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province, P.R. China
| | - Dongdong Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province, P.R. China
| | - Lei Zheng
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province, P.R. China
| | - Yingzhuan Zhan
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province, P.R. China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University No. 76, Yanta Weststreet, #54, Xi'an, Shaanxi Province, P.R. China
| |
Collapse
|
|
42
|
Champa D, Di Cristofano A. Modeling anaplastic thyroid carcinoma in the mouse. Discov Oncol 2014; 6:37-44. [PMID: 25420535 DOI: 10.1007/s12672-014-0208-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 11/12/2014] [Indexed: 02/07/2023] Open
Abstract
Anaplastic thyroid carcinoma is the least common form of thyroid cancer; however, it accounts for the majority of deaths associated with this family of malignancies. A number of genetically engineered immunocompetent mouse models recapitulating the genetic and histological features of anaplastic thyroid cancer have been very recently generated and represent an invaluable tool to dissect the mechanisms involved in the progression from indolent, well-differentiated tumors to aggressive, undifferentiated carcinomas and to identify novel therapeutic targets. In this review, we focus on the relevant characteristics associated with these models and on what we have learned in terms of anaplastic thyroid cancer biology, genetics, and response to targeted therapy.
Collapse
Affiliation(s)
- Devora Champa
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Room 302, Bronx, NY, 10461, USA
| | | |
Collapse
|
|
43
|
Grazia G, Vegetti C, Benigni F, Penna I, Perotti V, Tassi E, Bersani I, Nicolini G, Canevari S, Carlo-Stella C, Gianni AM, Mortarini R, Anichini A. Synergistic anti-tumor activity and inhibition of angiogenesis by cotargeting of oncogenic and death receptor pathways in human melanoma. Cell Death Dis 2014; 5:e1434. [PMID: 25275595 PMCID: PMC4649516 DOI: 10.1038/cddis.2014.410] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 08/11/2014] [Accepted: 08/18/2014] [Indexed: 12/11/2022]
Abstract
Improving treatment of advanced melanoma may require the development of effective strategies to overcome resistance to different anti-tumor agents and to counteract relevant pro-tumoral mechanisms in the microenvironment. Here we provide preclinical evidence that these goals can be achieved in most melanomas, by co-targeting of oncogenic and death receptor pathways, and independently of their BRAF, NRAS, p53 and PTEN status. In 49 melanoma cell lines, we found independent susceptibility profiles for response to the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor BEZ235 and the death receptor ligand TRAIL, supporting the rationale for their association. Drug interaction analysis indicated that a strong synergistic anti-tumor activity could be achieved by the three agents and the AZD6244–TRAIL association on 20/21 melanomas, including cell lines resistant to the inhibitors or to TRAIL. Mechanistically, synergy was explained by enhanced induction of caspase-dependent apoptosis, mitochondrial depolarization and modulation of key regulators of extrinsic and intrinsic cell death pathways, including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members. Moreover, silencing experiments confirmed the central role of Apollon downmodulation in promoting the apoptotic response of melanoma cells to the combinatorial treatments. In SCID mice, the AZD6244–TRAIL association induced significant growth inhibition of a tumor resistant to TRAIL and poorly responsive to AZD6244, with no detectable adverse events on body weight and tissue histology. Reduction in tumor volume was associated not only with promotion of tumor apoptosis but also with suppression of the pro-angiogenic molecules HIF1α, VEGFα, IL-8 and TGFβ1 and with inhibition of tumor angiogenesis. These results suggest that synergistic co-targeting of oncogenic and death receptor pathways can not only overcome melanoma resistance to different anti-tumor agents in vitro but can also promote pro-apoptotic effects and inhibition of tumor angiogenesis in vivo.
Collapse
Affiliation(s)
- G Grazia
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - C Vegetti
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - F Benigni
- San Raffaele Scientific Institute, URI, Milan, Italy
| | - I Penna
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - V Perotti
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - E Tassi
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - I Bersani
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - G Nicolini
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - S Canevari
- Functional Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - C Carlo-Stella
- 1] Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy [2] Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - A M Gianni
- Medical Oncology Unit 2, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - R Mortarini
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| | - A Anichini
- Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and Medical Oncology, Università degli Studi di Milano, Milan, Italy
| |
Collapse
|
|
44
|
Hu XX, Wang Y, Wang JXY. Handan Ganle inhibits PI3K/Akt signaling pathway in liver fibrosis in rats. Shijie Huaren Xiaohua Zazhi 2014; 22:1915-1920. [DOI: 10.11569/wcjd.v22.i14.1915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To observe the change of the PI3K/Akt signaling pathway in CCl4 induced liver fibrosis and to explore the effect of Handan Ganle on this signaling pathway in hepatic fibrosis in rats.
METHODS: Thirty SD rats were randomly divided into a normal control group, a liver fibrosis group and a Handan Ganle treated group. The rats of the liver fibrosis group and Handan Ganle treated group were treated by hypodermic injection of 40% CCl4 at 0.3 mL/100 g body weight to induce hepatic fibrosis. Then, the rats in the Handan Ganle group were treated with 1.0 g/kg Handan Ganle once daily for 8 weeks. The expression of Akt1 and phospho-Akt1 was detected by immunohistochemistry and Western blot, and the apoptosis of HSCs was determined by TUNEL assay.
RESULTS: Compared with the normal control group, the expression of Akt1 (2.73 ± 0.52 vs 9.60 ± 2.28, P < 0.01) and phospho-Akt1 (0.92 ± 0.40 vs 6.51 ± 1.39, P < 0.01) in the liver fibrosis group was increased. Handan Ganle treatment decreased the levels of Akt1 (9.60 ± 2.28 vs 5.36 ± 1.59, P < 0.01) and phospho-Akt1 (6.51 ± 1.39 vs 2.08 ± 0.85, P < 0.01) but increased the apoptosis of HSCs (1.07 ± 0.32 vs 4.24 ± 0.86, P < 0.01).
CONCLUSION: The PI3K/Akt signaling pathway may play an important role in CCl4 induced liver fibrosis. Handan Ganle can suppress this signaling pathway and increase the apoptosis of HSCs, which might be related with its anti-hepatic fibrosis activity.
Collapse
|