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1
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Chintalaramulu N, Singh DP, Sapkota B, Raman D, Alahari S, Francis J. Caveolin-1: an ambiguous entity in breast cancer. Mol Cancer 2025; 24:109. [PMID: 40197489 PMCID: PMC11974173 DOI: 10.1186/s12943-025-02297-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 03/07/2025] [Indexed: 04/10/2025] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer in women and the second leading cause of death from cancer among women. Metastasis is the major cause of BC-associated mortality. Accumulating evidence implicates Caveolin-1 (Cav-1), a structural protein of plasma membrane caveolae, in BC metastasis. Cav-1 exhibits a dual role, as both a tumor suppressor and promoter depending on the cellular context and BC subtype. This review highlights the role of Cav-1 in modulating glycolytic metabolism, tumor-stromal interactions, apoptosis, and senescence. Additionally, stromal Cav-1's expression is identified as a potential prognostic marker, offering insights into its contrasting roles in tumor suppression and progression. Furthermore, Cav-1's context-dependent effects are explored in BC subtypes including hormone receptor-positive, HER2-positive, and triple-negative BC (TNBC). The review further delves into the role of Cav-1 in regulating the metastatic cascade including extracellular matrix interactions, cell migration and invasion, and premetastatic niche formation. The later sections discuss the therapeutic targeting of Cav-1 by metabolic inhibitors such as betulinic acid and Cav-1 modulating compounds. While Cav-1 may be a potential biomarker and therapeutic target, its heterogeneous expression and context-specific activity necessitates further research to develop precise interventions. Future studies investigating the mechanistic role of Cav-1 in metastasis may pave the way for effective treatment of metastatic BC.
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Affiliation(s)
- Naveen Chintalaramulu
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | | | - Biplov Sapkota
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | - Dayanidhi Raman
- Department of Cell and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH, USA
| | | | - Joseph Francis
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
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2
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Liu Y, Corrales-Guerrero S, Kuo JC, Robb R, Nagy G, Cui T, Lee RJ, Williams TM. Improved Targeting and Safety of Doxorubicin through a Novel Albumin Binding Prodrug Approach. ACS OMEGA 2024; 9:977-987. [PMID: 38222540 PMCID: PMC10785662 DOI: 10.1021/acsomega.3c07163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 01/16/2024]
Abstract
Human serum albumin (HSA) improves the pharmacokinetic profile of drugs attached to it, making it an attractive carrier with proven clinical success. In our previous studies, we have shown that Caveolin-1 (Cav-1) and caveolae-mediated endocytosis play important roles in the uptake of HSA and albumin-bound drugs. Doxorubicin is an FDA-approved chemotherapeutic agent that is effective against multiple cancers, but its clinical applicability has been hampered by its high toxicity levels. In this study, a doxorubicin-prodrug was developed that could independently and avidly bind HSA in circulation, called IPBA-Dox. We first developed and characterized IPBA-Dox and confirmed that it can bind albumin in vitro while retaining a potent cytotoxic effect. We then verified that it efficiently binds to HSA in circulation, leading to an improvement in the pharmacokinetic profile of the drug. In addition, we tested our prodrug for Cav-1 selectivity and found that it preferentially affects cells that express relatively higher levels of Cav-1 in vitro and in vivo. Moreover, we found that our compound was well tolerated in vivo at concentrations at which doxorubicin was lethal. Altogether, we have developed a doxorubicin-prodrug that can successfully bind HSA, retaining a strong cytotoxic effect that preferentially targets Cav-1 positive cells while improving the general tolerability of the drug.
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Affiliation(s)
- Yang Liu
- Division
of Pharmaceutics and Pharmacology, The Ohio
State University, Columbus, Ohio 43210-1132, United States
| | - Sergio Corrales-Guerrero
- Biomedical
Sciences Graduate Program, The Ohio State
University, Columbus, Ohio 43210-1132, United States
| | - Jimmy C. Kuo
- Division
of Pharmaceutics and Pharmacology, The Ohio
State University, Columbus, Ohio 43210-1132, United States
| | - Ryan Robb
- University
of North Carolina, Chapel
Hill, North Carolina 27514-3916, United States
| | - Gregory Nagy
- Biomedical
Sciences Graduate Program, The Ohio State
University, Columbus, Ohio 43210-1132, United States
| | - Tiantian Cui
- Department
of Radiation Oncology, City of Hope National
Medical Center, Duarte, California 91010, United States
| | - Robert J. Lee
- Division
of Pharmaceutics and Pharmacology, The Ohio
State University, Columbus, Ohio 43210-1132, United States
| | - Terence M. Williams
- Department
of Radiation Oncology, City of Hope National
Medical Center, Duarte, California 91010, United States
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3
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D’Alessio A. Unraveling the Cave: A Seventy-Year Journey into the Caveolar Network, Cellular Signaling, and Human Disease. Cells 2023; 12:2680. [PMID: 38067108 PMCID: PMC10705299 DOI: 10.3390/cells12232680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/16/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023] Open
Abstract
In the mid-1950s, a groundbreaking discovery revealed the fascinating presence of caveolae, referred to as flask-shaped invaginations of the plasma membrane, sparking renewed excitement in the field of cell biology. Caveolae are small, flask-shaped invaginations in the cell membrane that play crucial roles in diverse cellular processes, including endocytosis, lipid homeostasis, and signal transduction. The structural stability and functionality of these specialized membrane microdomains are attributed to the coordinated activity of scaffolding proteins, including caveolins and cavins. While caveolae and caveolins have been long appreciated for their integral roles in cellular physiology, the accumulating scientific evidence throughout the years reaffirms their association with a broad spectrum of human disorders. This review article aims to offer a thorough account of the historical advancements in caveolae research, spanning from their initial discovery to the recognition of caveolin family proteins and their intricate contributions to cellular functions. Furthermore, it will examine the consequences of a dysfunctional caveolar network in the development of human diseases.
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Affiliation(s)
- Alessio D’Alessio
- Sezione di Istologia ed Embriologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Roma, Italy;
- Fondazione Policlinico Universitario “Agostino Gemelli”, IRCCS, 00168 Rome, Italy
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4
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Hwang N, Yoon BK, Chun KH, Kim H, Lee Y, Kim JW, Jeon H, Kim TH, Kim MY, Fang S, Cheong JH, Kim JW. Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer. Exp Mol Med 2023; 55:2461-2472. [PMID: 37919422 PMCID: PMC10689497 DOI: 10.1038/s12276-023-01109-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/20/2023] [Accepted: 07/31/2023] [Indexed: 11/04/2023] Open
Abstract
Despite advances in cancer therapy, the clinical outcome of patients with gastric cancer remains poor, largely due to tumor heterogeneity. Thus, finding a hidden vulnerability of clinically refractory subtypes of gastric cancer is crucial. Here, we report that chemoresistant gastric cancer cells rely heavily on endocytosis, facilitated by caveolin-1, for survival. caveolin-1 was highly upregulated in the most malignant stem-like/EMT/mesenchymal (SEM)-type gastric cancer cells, allowing caveolin-1-mediated endocytosis and utilization of extracellular proteins via lysosomal degradation. Downregulation of caveolin-1 alone was sufficient to induce cell death in SEM-type gastric cancer cells, emphasizing its importance as a survival mechanism. Consistently, chloroquine, a lysosomal inhibitor, successfully blocked caveolin-1-mediated endocytosis, leading to the marked suppression of tumor growth in chemorefractory gastric cancer cells in vitro, including patient-derived organoids, and in vivo. Together, our findings suggest that caveolin-1-mediated endocytosis is a key metabolic pathway for gastric cancer survival and a potential therapeutic target.
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Affiliation(s)
- Nahee Hwang
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bo Kyung Yoon
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyu-Hye Chun
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyeonhui Kim
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoseob Lee
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Won Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyeonuk Jeon
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tae-Hyun Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Mi-Young Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sungsoon Fang
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Severance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
| | - Jae-Ho Cheong
- Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Department of R&D, Veraverse Inc., Seoul, Republic of Korea.
| | - Jae-Woo Kim
- Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Saldaña-Villa AK, Lara-Lemus R. The Structural Proteins of Membrane Rafts, Caveolins and Flotillins, in Lung Cancer: More Than Just Scaffold Elements. Int J Med Sci 2023; 20:1662-1670. [PMID: 37928877 PMCID: PMC10620868 DOI: 10.7150/ijms.87836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/25/2023] [Indexed: 11/07/2023] Open
Abstract
Lung cancer is one of the most frequently diagnosed cancers worldwide. Due to its late diagnosis, it remains the leading cause of cancer-related deaths. Despite it is mostly associated to tobacco smoking, recent data suggested that genetic factors are of the highest importance. In this context, different processes meaningful for the development and progression of lung cancer such endocytosis, protein secretion and signal transduction, are controlled by membrane rafts. These highly ordered membrane domains contain proteins such as caveolins and flotillins, which were traditionally considered scaffold proteins but have currently been given a preponderant role in lung cancer. Here, we summarize current knowledge regarding the involvement of caveolins and flotillins in lung cancer from a molecular point of view.
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Affiliation(s)
| | - Roberto Lara-Lemus
- Department of Molecular Biomedicine and Translational Research, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Villegas”. Mexico City, Mexico
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6
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Williams TM, Schneeweiss A, Jackisch C, Shen C, Weber KE, Fasching PA, Denkert C, Furlanetto J, Heinmöller E, Schmatloch S, Karn T, Szeto CW, van Mackelenbergh MT, Nekljudova V, Stickeler E, Soon-Shiong P, Schem C, Mairinger T, Müller V, Marmé F, Untch M, Loibl S. Caveolin Gene Expression Predicts Clinical Outcomes for Early-Stage HER2-Negative Breast Cancer Treated with Paclitaxel-Based Chemotherapy in the GeparSepto Trial. Clin Cancer Res 2023; 29:3384-3394. [PMID: 37432976 PMCID: PMC10530448 DOI: 10.1158/1078-0432.ccr-23-0362] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/20/2023] [Accepted: 07/07/2023] [Indexed: 07/13/2023]
Abstract
PURPOSE Caveolin-1 and -2 (CAV1/2) dysregulation are implicated in driving cancer progression and may predict response to nab-paclitaxel. We explored the prognostic and predictive potential of CAV1/2 expression for patients with early-stage HER2-negative breast cancer receiving neoadjuvant paclitaxel-based chemotherapy regimens, followed by epirubicin and cyclophosphamide. EXPERIMENTAL DESIGN We correlated tumor CAV1/2 RNA expression with pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) in the GeparSepto trial, which randomized patients to neoadjuvant paclitaxel- versus nab-paclitaxel-based chemotherapy. RESULTS RNA sequencing data were available for 279 patients, of which 74 (26.5%) were hormone receptor (HR)-negative, thus triple-negative breast cancer (TNBC). Patients treated with nab-paclitaxel with high CAV1/2 had higher probability of obtaining a pCR [CAV1 OR, 4.92; 95% confidence interval (CI), 1.70-14.22; P = 0.003; CAV2 OR, 5.39; 95% CI, 1.76-16.47; P = 0.003] as compared with patients with high CAV1/2 treated with solvent-based paclitaxel (CAV1 OR, 0.33; 95% CI, 0.11-0.95; P = 0.040; CAV2 OR, 0.37; 95% CI, 0.12-1.13; P = 0.082). High CAV1 expression was significantly associated with worse DFS and OS in paclitaxel-treated patients (DFS HR, 2.29; 95% CI, 1.08-4.87; P = 0.030; OS HR, 4.97; 95% CI, 1.73-14.31; P = 0.003). High CAV2 was associated with worse DFS and OS in all patients (DFS HR, 2.12; 95% CI, 1.23-3.63; P = 0.006; OS HR, 2.51; 95% CI, 1.22-5.17; P = 0.013), in paclitaxel-treated patients (DFS HR, 2.47; 95% CI, 1.12-5.43; P = 0.025; OS HR, 4.24; 95% CI, 1.48-12.09; P = 0.007) and in patients with TNBC (DFS HR, 4.68; 95% CI, 1.48-14.85; P = 0.009; OS HR, 10.43; 95% CI, 1.22-89.28; P = 0.032). CONCLUSIONS Our findings indicate high CAV1/2 expression is associated with worse DFS and OS in paclitaxel-treated patients. Conversely, in nab-paclitaxel-treated patients, high CAV1/2 expression is associated with increased pCR and no significant detriment to DFS or OS compared with low CAV1/2 expression.
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Affiliation(s)
- Terence M. Williams
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California, USA
| | | | | | - Changxian Shen
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California, USA
| | | | - Peter A. Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Carsten Denkert
- Institut für Pathologie Philipps-Universität Marburg, Marburg, Germany
| | | | | | | | - Thomas Karn
- Department of Gynecology and Obstetrics, Goethe University Frankfurt, Frankfurt, Germany
| | | | | | | | | | | | | | | | - Volkmar Müller
- Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | | | | | - Sibylle Loibl
- German Breast Group, Neu-Isenburg, Germany
- Centre for Haematology and Oncology, Bethanien Frankfurt/M, Germany
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7
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Tang Q, Wang S, Di Z, Li H, Xu K, Hu X, Di M. Identification and validation of a prognostic risk model based on caveolin family genes for breast cancer. Front Cell Dev Biol 2022; 10:822187. [PMID: 36147736 PMCID: PMC9485841 DOI: 10.3389/fcell.2022.822187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Breast cancer (BC) is the most vicious killer of women’s health and is accompanied by increased incidence and mortality rates worldwide. Many studies have demonstrated that caveolins (CAVs) were abnormally expressed in a variety of tumors and implicated in tumorigenesis and cancer progression. However, the role of CAVs in BC remains somewhat contentious.Methods: We comprehensively explored the expression and prognostic value of CAVs (CAV1-3) in BC utilizing public databases (ONCOMINE, TIMER, UALCAN, and TCGA databases). Then we constructed a prognostic model based on the expression profiles. Also, a prognostic nomogram was built to predict the overall survival (OS). We further investigated the relationship between this signature and immune cell infiltration and the mutational landscape in BC. The R package “pRRophetic” was used to predict chemotherapeutic response in BC patients. Finally, we employed loss-of-function approaches to validate the role of CAVs in BC.Results: We found that CAVs were significantly downregulated in various cancer types, especially in BC. Low CAV expression was closely related to the malignant clinicopathological characteristics and worse OS and relapse-free survival (RFS) in BC. Then we constructed a prognostic model based on the expression profiles of CAVs, which divided BC patients into two risk groups. The Kaplan–Meier analysis showed that patients in the high-risk group tend to have a poorer prognosis than those in the low-risk group. Multivariate analysis indicated that the risk score and stage were both independent prognostic factors for BC patients, suggesting a complementary value. The clinical profiles and risk module were used to construct a nomogram that could accurately predict the OS in BC. In addition, we found that patients in the low-risk group tend to have a relatively high immune status and a lower mutation event frequency compared to the high-risk group. Furthermore, this signature could predict the response to chemotherapy and immunotherapy. Finally, CAV depletion promoted the colony formation, migration, and invasion of BC cells.Conclusion: CAVs may serve as novel biomarkers and independent prognostic factors for BC patients. Also, the constructed signature based on CAVs may predict immunotherapeutic responses and provide a novel nomogram for precise outcome prediction of BC.
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Affiliation(s)
- Qiang Tang
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Shurui Wang
- School of Nursing Peking Union Medical College, Beijing, China
| | - Ziyang Di
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Huimin Li
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Kailiang Xu
- Department of Urology, Jingzhou Central Hospital, the Second Clinical Medical College, Yangtze University, Jingzhou, China
- *Correspondence: Maojun Di, ; Xin Hu, ; Kailiang Xu,
| | - Xin Hu
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, China
- *Correspondence: Maojun Di, ; Xin Hu, ; Kailiang Xu,
| | - Maojun Di
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, China
- *Correspondence: Maojun Di, ; Xin Hu, ; Kailiang Xu,
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Bittoni A, Giampieri R, Pecci F, Pinterpe G, Mandolesi A, Del Prete M, Zizzi A, Crocetti S, Liguori C, Mentrasti G, Cantini L, Pellei C, Bisonni R, Scarpelli M, Berardi R. Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients. Curr Oncol 2021; 28:3525-3536. [PMID: 34590611 PMCID: PMC8482160 DOI: 10.3390/curroncol28050303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/02/2021] [Accepted: 09/04/2021] [Indexed: 11/17/2022] Open
Abstract
Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.
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Affiliation(s)
- Alessandro Bittoni
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Riccardo Giampieri
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Federica Pecci
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Giada Pinterpe
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Alessandra Mandolesi
- Department of Pathological Anatomy and Histopathology, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, 60126 Ancona, Italy; (A.M.); (A.Z.); (M.S.)
| | - Michela Del Prete
- Medical Oncology Unit, Ospedale A. Murri, 63900 Fermo, Italy; (M.D.P.); (R.B.)
| | - Antonio Zizzi
- Department of Pathological Anatomy and Histopathology, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, 60126 Ancona, Italy; (A.M.); (A.Z.); (M.S.)
| | - Sonia Crocetti
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Carolina Liguori
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Giulia Mentrasti
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Luca Cantini
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
| | - Chiara Pellei
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
- Medical Oncology Unit, Ospedale Madonna del Soccorso, 63074 San Benedetto del Tronto, Italy
| | - Renato Bisonni
- Medical Oncology Unit, Ospedale A. Murri, 63900 Fermo, Italy; (M.D.P.); (R.B.)
| | - Marina Scarpelli
- Department of Pathological Anatomy and Histopathology, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, 60126 Ancona, Italy; (A.M.); (A.Z.); (M.S.)
| | - Rossana Berardi
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Università Politecnica delle Marche, 60126 Ancona, Italy; (A.B.); (R.G.); (F.P.); (G.P.); (S.C.); (C.L.); (G.M.); (L.C.); (C.P.)
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9
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Kaya S, Wiesmann N, Goldschmitt J, Krüger M, Al-Nawas B, Heider J. Differences in the expression of caveolin-1 isoforms in cancer-associated and normal fibroblasts of patients with oral squamous cell carcinoma. Clin Oral Investig 2021; 25:5823-5831. [PMID: 33774714 PMCID: PMC8443514 DOI: 10.1007/s00784-021-03887-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/12/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES For many years, tumor development has been viewed as a cell-autonomous process; however, today we know that the tumor microenvironment (TME) and especially cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression. Caveolin-1 (Cav-1) is a scaffolding protein which is involved in several cancer-associated processes as important component of the caveolae. Our goal was to shed light on the expression of the two different isoforms of Cav-1 in normal fibroblasts (NFs) and CAFs of patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS Fibroblasts from normal mucosa and CAFs were isolated and propagated in vitro. Gene expression of the different Cav-1 isoforms was assessed via quantitative real-time PCR (qPCR) and supplemented by protein expression analysis. RESULTS We could show that the Cav-1β isoform is more highly expressed in NFs and CAFs compared to Cav-1α. Furthermore, the different Cav-1 isoforms tended to be differently expressed in different tumor stages. However, this trend could not be seen consistently, which is in line with the ambiguous role of Cav-1 in tumor progression described in literature. Western blotting furthermore revealed that NFs and CAFs might differ in the oligomerization profile of the Cav-1 protein. CONCLUSION These differences in expression of Cav-1 between NFs and CAFs of patients with OSCC confirm that the protein might play a role in tumor progression and is of interest for further analyses. CLINICAL RELEVANCE Our findings support a possible role of the two isoforms of Cav-1 in the malignant transformation of OSCC.
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Affiliation(s)
- S Kaya
- Department of Oral and Maxillofacial Surgery Plastic Surgery, University Medical Center of the Johannes Gutenberg-University of Mainz, Augustusplatz 2, 55131, Mainz, Germany
| | - Nadine Wiesmann
- Department of Oral and Maxillofacial Surgery Plastic Surgery, University Medical Center of the Johannes Gutenberg-University of Mainz, Augustusplatz 2, 55131, Mainz, Germany. .,Molecular Tumor Biology, Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg-University, Langenbeckstraße 1, 55131, Mainz, Germany.
| | - J Goldschmitt
- Department of Oral and Maxillofacial Surgery Plastic Surgery, University Medical Center of the Johannes Gutenberg-University of Mainz, Augustusplatz 2, 55131, Mainz, Germany
| | - M Krüger
- Department of Oral and Maxillofacial Surgery Plastic Surgery, University Medical Center of the Johannes Gutenberg-University of Mainz, Augustusplatz 2, 55131, Mainz, Germany
| | - B Al-Nawas
- Department of Oral and Maxillofacial Surgery Plastic Surgery, University Medical Center of the Johannes Gutenberg-University of Mainz, Augustusplatz 2, 55131, Mainz, Germany
| | - J Heider
- Department of Oral and Maxillofacial Surgery Plastic Surgery, University Medical Center of the Johannes Gutenberg-University of Mainz, Augustusplatz 2, 55131, Mainz, Germany
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10
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Luanpitpong S, Rodboon N, Samart P, Vinayanuwattikun C, Klamkhlai S, Chanvorachote P, Rojanasakul Y, Issaragrisil S. A novel TRPM7/O-GlcNAc axis mediates tumour cell motility and metastasis by stabilising c-Myc and caveolin-1 in lung carcinoma. Br J Cancer 2020; 123:1289-1301. [PMID: 32684624 PMCID: PMC7555538 DOI: 10.1038/s41416-020-0991-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 06/01/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Calcium is an essential signal transduction element that has been associated with aggressive behaviours in several cancers. Cell motility is a prerequisite for metastasis, the major cause of lung cancer death, yet its association with calcium signalling and underlying regulatory axis remains an unexplored area. METHODS Bioinformatics database analyses were employed to assess correlations between calcium influx channels and clinical outcomes in non-small cell lung cancer (NSCLC). Functional and regulatory roles of influx channels in cell migration and invasion were conducted and experimental lung metastasis was examined using in vivo live imaging. RESULTS High expression of TRPM7 channel correlates well with the low survival rate of patients and high metastatic potential. Inhibition of TRPM7 suppresses cell motility in various NSCLC cell lines and patient-derived primary cells and attenuates experimental lung metastases. Mechanistically, TRPM7 acts upstream of O-GlcNAcylation, a post-translational modification and a crucial sensor for metabolic changes. We reveal for the first time that caveolin-1 and c-Myc are favourable molecular targets of TRPM7/O-GlcNAc that regulates NSCLC motility. O-GlcNAcylation of caveolin-1 and c-Myc promotes protein stability by interfering with their ubiquitination and proteasomal degradation. CONCLUSIONS TRPM7/O-GlcNAc axis represents a potential novel target for lung cancer therapy that may overcome metastasis.
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Affiliation(s)
- Sudjit Luanpitpong
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Napachai Rodboon
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Parinya Samart
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chanida Vinayanuwattikun
- Department of Medicine, Division of Medical Oncology, Faculty of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Siwaporn Klamkhlai
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Yon Rojanasakul
- WVU Cancer Institute and Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA
| | - Surapol Issaragrisil
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Department of Medicine, Division of Hematology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- Bangkok Hematology Center, Wattanosoth Hospital, BDMS Center of Excellence for Cancer, Bangkok, Thailand
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11
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Xu D, Zhang J, Xu H, Zhang Y, Chen W, Gao R, Dehmer M. Multi-scale supervised clustering-based feature selection for tumor classification and identification of biomarkers and targets on genomic data. BMC Genomics 2020; 21:650. [PMID: 32962626 PMCID: PMC7510277 DOI: 10.1186/s12864-020-07038-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 08/30/2020] [Indexed: 12/19/2022] Open
Abstract
Background The small number of samples and the curse of dimensionality hamper the better application of deep learning techniques for disease classification. Additionally, the performance of clustering-based feature selection algorithms is still far from being satisfactory due to their limitation in using unsupervised learning methods. To enhance interpretability and overcome this problem, we developed a novel feature selection algorithm. In the meantime, complex genomic data brought great challenges for the identification of biomarkers and therapeutic targets. The current some feature selection methods have the problem of low sensitivity and specificity in this field. Results In this article, we designed a multi-scale clustering-based feature selection algorithm named MCBFS which simultaneously performs feature selection and model learning for genomic data analysis. The experimental results demonstrated that MCBFS is robust and effective by comparing it with seven benchmark and six state-of-the-art supervised methods on eight data sets. The visualization results and the statistical test showed that MCBFS can capture the informative genes and improve the interpretability and visualization of tumor gene expression and single-cell sequencing data. Additionally, we developed a general framework named McbfsNW using gene expression data and protein interaction data to identify robust biomarkers and therapeutic targets for diagnosis and therapy of diseases. The framework incorporates the MCBFS algorithm, network recognition ensemble algorithm and feature selection wrapper. McbfsNW has been applied to the lung adenocarcinoma (LUAD) data sets. The preliminary results demonstrated that higher prediction results can be attained by identified biomarkers on the independent LUAD data set, and we also structured a drug-target network which may be good for LUAD therapy. Conclusions The proposed novel feature selection method is robust and effective for gene selection, classification, and visualization. The framework McbfsNW is practical and helpful for the identification of biomarkers and targets on genomic data. It is believed that the same methods and principles are extensible and applicable to other different kinds of data sets.
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Affiliation(s)
- Da Xu
- School of Mathematics and Statistics, Shandong University, Weihai, 264209, China
| | - Jialin Zhang
- School of Mathematics and Statistics, Shandong University, Weihai, 264209, China
| | - Hanxiao Xu
- School of Mathematics and Statistics, Shandong University, Weihai, 264209, China
| | - Yusen Zhang
- School of Mathematics and Statistics, Shandong University, Weihai, 264209, China.
| | - Wei Chen
- School of Mathematics and Statistics, Shandong University, Weihai, 264209, China
| | - Rui Gao
- School of Control Science and Engineering, Shandong University, Jinan, 250061, China
| | - Matthias Dehmer
- Institute for Intelligent Production, Faculty for Management, University of Applied Sciences Upper Austria, Steyr Campus, Steyr, Austria.,College of Computer and Control Engineering, Nankai University, Tianjin, 300071, China.,Department of Mechatronics and Biomedical Computer Science, UMIT, Hall in Tyrol, Austria
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12
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Caveolin-1 Knockdown Decreases SMMC7721 Human Hepatocellular Carcinoma Cell Invasiveness by Inhibiting Vascular Endothelial Growth Factor-Induced Angiogenesis. Can J Gastroenterol Hepatol 2020; 2020:8880888. [PMID: 32676485 PMCID: PMC7336196 DOI: 10.1155/2020/8880888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/03/2020] [Accepted: 06/08/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Recently, several studies have demonstrated that caveolin-1 overexpression is involved in apoptosis resistance, angiogenesis, and invasiveness in hepatocellular carcinoma (HCC). However, the mechanisms underlying caveolin-1-mediated tumor progression remain unclear. Methodogy. Lentiviral vectors were used to construct caveolin-1 small interfering RNA- (siRNA-) expressing cells. Secreted VEGF levels in SMMC7721 cells were evaluated by enzyme-linked immunosorbent assay (ELISA). SMMC7721 cell proliferation, cycle, apoptosis, and invasiveness were detected by MTT, flow cytometry, Annexin V-FITC/PI, and invasion assay, respectively. Phospho-eNOS levels in human umbilical vein endothelial cells (HUVECs) cocultured with SMMC7721 cell supernatants were analyzed by Western blot. Capillary-like tubule formation assay was performed to analyze endothelial tubular structure formation in HUVECs treated with supernatants from caveolin-1 siRNA-expressing SMMC7721 cells. SMMC7721 implantation and growth in nude mice were observed. Angiogenesis in vivo was analyzed by immunohistochemical angiogenesis assay. RESULTS Caveolin-1 siRNA-expressing SMMC7721 cells secreted reduced levels of VEGF. Caveolin-1 RNAi also caused an inhibition of SMMC7721 cell proliferation and cell cycle progression that was accompanied by increased apoptosis. Supernatants from caveolin-1 siRNA-expressing SMMC7721 cells inhibited cell cycle progression and decreased phospho-eNOS levels in HUVECs. Endothelial tubular structure formation in HUVECs treated with supernatants from caveolin-1 siRNA-expressing SMMC7721 cells was considerably reduced. Caveolin-1 siRNA-expressing SMMC7721 cells also showed reduced tumorigenicity and angiogenesis induction in vivo. CONCLUSION Our results reveal a novel mechanism, whereby caveolin-1 positively regulates human HCC cell invasiveness by coordinating VEGF-induced angiogenesis.
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13
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Raudenska M, Gumulec J, Balvan J, Masarik M. Caveolin-1 in oncogenic metabolic symbiosis. Int J Cancer 2020; 147:1793-1807. [PMID: 32196654 DOI: 10.1002/ijc.32987] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/28/2020] [Accepted: 03/16/2020] [Indexed: 12/18/2022]
Abstract
Metabolic phenotypes of cancer cells are heterogeneous and flexible as a tumor mass is a hurriedly evolving system capable of constant adaptation to oxygen and nutrient availability. The exact type of cancer metabolism arises from the combined effects of factors intrinsic to the cancer cells and factors proposed by the tumor microenvironment. As a result, a condition termed oncogenic metabolic symbiosis in which components of the tumor microenvironment (TME) promote tumor growth often occurs. Understanding how oncogenic metabolic symbiosis emerges and evolves is crucial for perceiving tumorigenesis. The process by which tumor cells reprogram their TME involves many mechanisms, including changes in intercellular communication, alterations in metabolic phenotypes of TME cells, and rearrangement of the extracellular matrix. It is possible that one molecule with a pleiotropic effect such as Caveolin-1 may affect many of these pathways. Here, we discuss the significance of Caveolin-1 in establishing metabolic symbiosis in TME.
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Affiliation(s)
- Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jaromir Gumulec
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic
| | - Jan Balvan
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic
| | - Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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14
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Shi YB, Li J, Lai XN, Jiang R, Zhao RC, Xiong LX. Multifaceted Roles of Caveolin-1 in Lung Cancer: A New Investigation Focused on Tumor Occurrence, Development and Therapy. Cancers (Basel) 2020; 12:cancers12020291. [PMID: 31991790 PMCID: PMC7073165 DOI: 10.3390/cancers12020291] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/13/2020] [Accepted: 01/22/2020] [Indexed: 12/26/2022] Open
Abstract
Lung cancer is one of the most common and malignant cancers with extremely high morbidity and mortality in both males and females. Although traditional lung cancer treatments are fast progressing, there are still limitations. Caveolin-1 (Cav-1), a main component of caveolae, participates in multiple cellular events such as immune responses, endocytosis, membrane trafficking, cellular signaling and cancer progression. It has been found tightly associated with lung cancer cell proliferation, migration, apoptosis resistance and drug resistance. In addition to this, multiple bioactive molecules have been confirmed to target Cav-1 to carry on their anti-tumor functions in lung cancers. Cav-1 can also be a predictor for lung cancer patients’ prognosis. In this review, we have summarized the valuable research on Cav-1 and lung cancer in recent years and discussed the multifaceted roles of Cav-1 on lung cancer occurrence, development and therapy, hoping to provide new insights into lung cancer treatment.
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Affiliation(s)
- Yu-Bo Shi
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (Y.-B.S.); (J.L.); (X.-N.L.); (R.-C.Z.)
- Queen Mary School, Jiangxi Medical College of Nanchang University, Nanchang 330006, China;
| | - Jun Li
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (Y.-B.S.); (J.L.); (X.-N.L.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Xing-Ning Lai
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (Y.-B.S.); (J.L.); (X.-N.L.); (R.-C.Z.)
- Second Clinical Medical College, Nanchang University, Nanchang 330006, China
| | - Rui Jiang
- Queen Mary School, Jiangxi Medical College of Nanchang University, Nanchang 330006, China;
| | - Rui-Chen Zhao
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (Y.-B.S.); (J.L.); (X.-N.L.); (R.-C.Z.)
- Queen Mary School, Jiangxi Medical College of Nanchang University, Nanchang 330006, China;
| | - Li-Xia Xiong
- Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; (Y.-B.S.); (J.L.); (X.-N.L.); (R.-C.Z.)
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang 330006, China
- Correspondence: ; Tel.: +86-791-8636-0556
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15
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Kato K, Miyazawa H, Kobayashi H, Noguchi N, Lambert D, Kawashiri S. Caveolin-1 Expression at Metastatic Lymph Nodes Predicts Unfavorable Outcome in Patients with Oral Squamous Cell Carcinoma. Pathol Oncol Res 2020; 26:2105-2113. [PMID: 31907776 DOI: 10.1007/s12253-019-00791-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 12/30/2019] [Indexed: 12/17/2022]
Abstract
We evaluated the clinical and prognostic value of the protein expression of caveolin-1 (CAV1) and p16 at the primary site and metastatic lymph nodes of oral squamous cell carcinoma (OSCC). Primary site specimens from 80 OSCC cases were randomly selected and lymph node specimens from 15 preserved metastatic lymph nodes from among those patients were selected for examination. We evaluated the CAV1 and p16 expression at both the primary site and metastatic lymph nodes, and analyzed the patients' clinicopathological data in relation to CAV1 and p16 expression. Our analysis revealed significant positive correlations between CAV1 expression at the primary site and pathological metastasis, cell differentiation, and mode of invasion (p = 0.019, p = 0.002, p = 0.015, respectively), but p16 expression was not associated with any clinicopathological factors. Patients with high CAV1 expression at the primary sites showed significantly worse prognoses than those with low or negative CAV1 expression (p = 0.002), and multivariate analysis showed that the T classification and CAV1 expression were independent OSCC prognostic factors. CAV1 expression was also present in the metastatic lymph nodes of the OSCC cases with particularly poor differentiation and high invasive grade, and patients with CAV1-positive metastatic lymph nodes showed significantly worse prognoses than those with CAV1-negative metastatic lymph nodes (p = 0.018). CAV1 may activate metastaticity and the invasive capacity of OSCC cells. CAV1 expression, particularly at metastatic lymph nodes, predicts a worse outcome for OSCC, suggesting that CAV1 could be used as a prognostic marker for OSCC.
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Affiliation(s)
- Koroku Kato
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
| | - Hiroki Miyazawa
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Hisano Kobayashi
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Natsuyo Noguchi
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
| | - Daniel Lambert
- Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
| | - Shuichi Kawashiri
- Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan
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16
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Gong Y, Yang Y, Tian S, Chen H. Different Role of Caveolin-1 Gene in the Progression of Gynecological Tumors. Asian Pac J Cancer Prev 2019; 20:3259-3268. [PMID: 31759347 PMCID: PMC7062999 DOI: 10.31557/apjcp.2019.20.11.3259] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Indexed: 12/13/2022] Open
Abstract
Caveolin-1 (Cav-1), an integral membrane protein, is a principal component of caveolae and has been reported to play a promoting or inhibiting role in cancer progression. Gynecologic tumor is a group of tumors that affect the tissue and organs of the female reproductive system, especially cervical cancer. Cervical cancer, as one of the most common cancers, severely affects female health in developing countries in particular because of its high morbidity and mortality. This review summarizes some mechanisms of Cav-1 in the development and progression of gynecological tumors. The role of Cav-1 in tumorigenesis, including dysregulation of cell cycle, apoptosis and autophagy, adhesion, invasion, and metastasis, such as the formation of invadopodia and matrix metalloproteinase degradation are presented in detail. In addition, Cav-1 modulates autophagy and the formation of invadopodia and target regulated by miRNAs to affect tumor progress. Taken together, we find that, no matter Cav-1 expression in the tumor or stromal cells , Cav-1 has paradoxical role in different types of gynecological tumors in vivo or in vitro and even in the same tumor from the same organ.
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Affiliation(s)
- Yan Gong
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China
| | - Yuhan Yang
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, P. R. China
| | - Sufang Tian
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China
| | - Honglei Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China
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17
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Ali A, Levantini E, Fhu CW, Teo JT, Clohessy JG, Goggi JL, Wu CS, Chen L, Chin TM, Tenen DG. CAV1 - GLUT3 signaling is important for cellular energy and can be targeted by Atorvastatin in Non-Small Cell Lung Cancer. Am J Cancer Res 2019; 9:6157-6174. [PMID: 31534543 PMCID: PMC6735519 DOI: 10.7150/thno.35805] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 07/28/2019] [Indexed: 02/06/2023] Open
Abstract
Background: The development of molecular targeted therapies, such as EGFR-TKIs, has positively impacted the management of EGFR mutated NSCLC. However, patients with innate and acquired resistance to EGFR-TKIs still face limited effective therapeutic options. Statins are the most frequently prescribed anti-cholesterol agents and have been reported to inhibit the progression of various malignancies, including in lung. However, the mechanism by which statin exerts its anti-cancer effects is unclear. This study is designed to investigate the anti-proliferative effects and identify the mechanism-of-action of statins in NSCLC. Methods: In this study, the anti-tumoral properties of Atorvastatin were investigated in NSCLC utilizing cell culture system and in vivo models. Results: We demonstrate a link between elevated cellular cholesterol and TKI-resistance in NSCLC, which is independent of EGFR mutation status. Atorvastatin suppresses growth by inhibiting Cav1 expression in tumors in cell culture system and in in vivo models. Subsequent interrogations demonstrate an oncogenic physical interaction between Cav1 and GLUT3, and glucose uptake found distinctly in TKI-resistant NSCLC and this may be due to changes in the physical properties of Cav1 favoring GLUT3 binding in which significantly stronger Cav1 and GLUT3 physical interactions were observed in TKI-resistant than in TKI-sensitive NSCLC cells. Further, the differential effects of atorvastatin observed between EGFR-TKI resistant and sensitive cells suggest that EGFR mutation status may influence its actions. Conclusions: This study reveals the inhibition of oncogenic role of Cav1 in GLUT3-mediated glucose uptake by statins and highlights its potential impact to overcome NSCLC with EGFR-TKI resistance.
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18
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Cell Intrinsic and Extrinsic Mechanisms of Caveolin-1-Enhanced Metastasis. Biomolecules 2019; 9:biom9080314. [PMID: 31362353 PMCID: PMC6723107 DOI: 10.3390/biom9080314] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/17/2019] [Accepted: 07/25/2019] [Indexed: 12/19/2022] Open
Abstract
Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. Different mechanisms are summarized illustrating how CAV1 promotes such traits upon expression in cancer cells (intrinsic mechanisms). More recently, it has become apparent that CAV1 is also a secreted protein that can be included into exosomes where it plays a significant role in determining cargo composition. Thus, we will also discuss how CAV1 containing exosomes from metastatic cells promote malignant traits in more benign recipient cells (extrinsic mechanisms). This ability appears, at least in part, attributable to the transfer of specific cargos present due to CAV1 rather than the transfer of CAV1 itself. The evolution of how our perception of CAV1 function has changed since its discovery is summarized graphically in a time line figure.
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19
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Lee PJ, Park HJ, Cho N, Kim HP. 3,5-Diethoxy-3'-Hydroxyresveratrol (DEHR) Ameliorates Liver Fibrosis via Caveolin-1 Activation in Hepatic Stellate Cells and in a Mouse Model of Bile Duct Ligation Injury. Molecules 2018; 23:molecules23112833. [PMID: 30384491 PMCID: PMC6278252 DOI: 10.3390/molecules23112833] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/27/2018] [Accepted: 10/29/2018] [Indexed: 11/29/2022] Open
Abstract
Hepatic stellate cells (HSCs) are involved in the pathogenesis of liver fibrosis. Resveratrol, 3,5,4′-trihydroxystilbene, is a dietary polyphenol found in natural food products. Here, we evaluated the anti-proliferative effects of a synthetic resveratrol derivative, 3,5-diethoxy-3′-hydroxyresveratrol (DEHR), on HSCs. Flow cytometry and Western blot analyses showed that DEHR induces apoptosis through the upregulation of cleaved caspase-3 and poly (ADP-ribose) polymerase expression and reduction in the level of an anti-apoptotic protein B-cell lymphoma 2 (Bcl2). As caveolin-1 (CAV1), a competitive inhibitor of heme oxygenase 1 (HO-1), is related to apoptotic proteins in hepatic cells, we focused on the role of CAV1 in DEHR-induced apoptosis in HSCs through Western blot analyses. Our results showed that the inhibitory effect of DEHR on cell viability was stronger in HO-1 siRNA-transfected cells but weakened in CAV1 siRNA-transfected cells. Collagen concentration was significantly reduced, whereas CAV1 expression increased after treatment of a bile duct ligation injury-induced liver fibrosis model with DEHR for four weeks. We confirmed that DEHR treatment significantly reduced fibrous hyperplasia around the central veins, using hematoxylin and eosin and Sirius red staining. DEHR ameliorates liver fibrosis in vitro and in vivo, possibly through a mechanism involving CAV1.
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Affiliation(s)
- Phil Jun Lee
- College of Pharmacy, Ajou University, Suwon 16499, Korea.
- Ilsong Institute of Life Science, Jung-gu, Gwan-yangdong 431-060, Korea.
| | - Hye-Jin Park
- College of Pharmacy, Ajou University, Suwon 16499, Korea.
| | - Namki Cho
- College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Korea.
| | - Hong Pyo Kim
- College of Pharmacy, Ajou University, Suwon 16499, Korea.
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20
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Bignon E, Allega MF, Lucchetta M, Tiberti M, Papaleo E. Computational Structural Biology of S-nitrosylation of Cancer Targets. Front Oncol 2018; 8:272. [PMID: 30155439 PMCID: PMC6102371 DOI: 10.3389/fonc.2018.00272] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 07/02/2018] [Indexed: 12/15/2022] Open
Abstract
Nitric oxide (NO) plays an essential role in redox signaling in normal and pathological cellular conditions. In particular, it is well known to react in vivo with cysteines by the so-called S-nitrosylation reaction. S-nitrosylation is a selective and reversible post-translational modification that exerts a myriad of different effects, such as the modulation of protein conformation, activity, stability, and biological interaction networks. We have appreciated, over the last years, the role of S-nitrosylation in normal and disease conditions. In this context, structural and computational studies can help to dissect the complex and multifaceted role of this redox post-translational modification. In this review article, we summarized the current state-of-the-art on the mechanism of S-nitrosylation, along with the structural and computational studies that have helped to unveil its effects and biological roles. We also discussed the need to move new steps forward especially in the direction of employing computational structural biology to address the molecular and atomistic details of S-nitrosylation. Indeed, this redox modification has been so far an underappreciated redox post-translational modification by the computational biochemistry community. In our review, we primarily focus on S-nitrosylated proteins that are attractive cancer targets due to the emerging relevance of this redox modification in a cancer setting.
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Affiliation(s)
- Emmanuelle Bignon
- Computational Biology Laboratory Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Maria Francesca Allega
- Computational Biology Laboratory Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Marta Lucchetta
- Computational Biology Laboratory Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Matteo Tiberti
- Computational Biology Laboratory Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Elena Papaleo
- Computational Biology Laboratory Danish Cancer Society Research Center, Copenhagen, Denmark.,Translational Disease Systems Biology, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research University of Copenhagen, Copenhagen, Denmark
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21
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Guerrero S, Díaz-García VM, Contreras-Orellana P, Lara P, Palma S, Guzman F, Lobos-Gonzalez L, Cárdenas A, Rojas-Silva X, Muñoz L, Leyton L, Kogan MJ, Quest AF. Gold nanoparticles as tracking devices to shed light on the role of caveolin-1 in early stages of melanoma metastasis. Nanomedicine (Lond) 2018; 13:1447-1462. [PMID: 29972676 DOI: 10.2217/nnm-2017-0390] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM To track early events during lung metastasis, we labeled cells expressing (B16F10CAV1) or lacking CAV1 (B16F10mock) with gold nanoparticles conjugated to the peptide TAT (AuNPs-PEG-TAT). METHODS B16F10 expressing or lacking CAV1 were labeled with AuNPs-PEG-TAT. The physicochemical properties and cytotoxicity of these nanoparticles, as well as their effects on migration and invasiveness of B16F10 cells in vitro were evaluated. Ex vivo lung distribution of the labeled cells after tail vein injection into C57BL/6 mice was examined. RESULTS AuNPs-PEG-TAT did not affect B16F10 viability, migration and invasiveness. The metastatic and tumorigenic capability of the labeled B16F10 was also not modified in comparison to unlabeled B16F10 cells. CAV1 expression favored the retention of B16F10 cells in the lungs of mice 2 h post injection, suggesting CAV1 promoted adherence to endothelial cells and transendothelial migration. CONCLUSIONS We developed a protocol to label B16F10 cells with AuNPs-PEG-TAT that permits subsequent tracking of cells in mice. CAV1 overexpression was found to increase retention and transendothelial migration of B16F10 cells in the lung.
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Affiliation(s)
- Simón Guerrero
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile
| | - Victor Manuel Díaz-García
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile.,Facultad de Ingeniería y Tecnología, Universidad San Sebastián, Lientur 1457, Concepción 4080871, Chile
| | - Pamela Contreras-Orellana
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile
| | - Pablo Lara
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile.,Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Chile
| | - Sujey Palma
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile.,Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Chile
| | - Fanny Guzman
- Núcleo de Biotecnología Curauma (NBC), Universidad Católica de Valparaíso, Av. Universidad 330, Curauma, Valparaíso, Chile
| | - Lorena Lobos-Gonzalez
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile.,Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Avenida Las Condes 12.438, Lo Barnechea Santiago, Chile
| | - Areli Cárdenas
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile.,Escuela de Obstetricia y Puericultura, Facultad de Salud, Universidad Bernardo OHiggins, Avenida Viel 1497, Santiago, Chile
| | - Ximena Rojas-Silva
- Laboratorio de Análisis por Activación Neutrónica, Comisión Chilena de Energía Nuclear (CChEN), Nueva Bilbao 12501, Santiago, Chile
| | - Luis Muñoz
- Laboratorio de Análisis por Activación Neutrónica, Comisión Chilena de Energía Nuclear (CChEN), Nueva Bilbao 12501, Santiago, Chile
| | - Lisette Leyton
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile
| | - Marcelo J Kogan
- Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile.,Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago, Chile
| | - Andrew Fg Quest
- Laboratory of Cellular Communication, Program of Cell & Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago, Chile.,Center for Studies on Exercise Metabolism & Cancer (CEMC), University of Chile, Av. Independencia 1027, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964, Independencia, Santiago, Chile
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22
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Abstract
Resistance of solid tumors to chemo- and radiotherapy remains a major obstacle in anti-cancer treatment. Herein, the membrane protein caveolin-1 (CAV1) came into focus as it is highly expressed in many tumors and high CAV1 levels were correlated with tumor progression, invasion and metastasis, and thus a worse clinical outcome. Increasing evidence further indicates that the heterogeneous tumor microenvironment, also known as the tumor stroma, contributes to therapy resistance resulting in poor clinical outcome. Again, CAV1 seems to play an important role in modulating tumor host interactions by promoting tumor growth, metastasis, therapy resistance and cell survival. However, the mechanisms driving stroma-mediated tumor growth and radiation resistance remain to be clarified. Understanding these interactions and thus, targeting CAV1 may offer a novel strategy for preventing cancer therapy resistance and improving clinical outcomes. In this review, we will summarize the resistance-promoting effects of CAV1 in tumors, and emphasize its role in the tumor-stroma communication as well as the resulting malignant phenotype of epithelial tumors.
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Affiliation(s)
- Julia Ketteler
- Institute for Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Diana Klein
- Institute for Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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23
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Díaz-Valdivia NI, Calderón CC, Díaz JE, Lobos-González L, Sepulveda H, Ortíz RJ, Martinez S, Silva V, Maldonado HJ, Silva P, Wehinger S, Burzio VA, Torres VA, Montecino M, Leyton L, Quest AFG. Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells. Oncotarget 2017; 8:111943-111965. [PMID: 29340103 PMCID: PMC5762371 DOI: 10.18632/oncotarget.22955] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 11/16/2017] [Indexed: 12/20/2022] Open
Abstract
Expression of the scaffolding protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic cancer cells. Yet, CAV1 also functions as a tumor suppressor in early stages of cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during chemotherapy might expose cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits. Here, we used in vitro [2D, invasion] and in vivo (metastasis) assays, as well as genetic and biochemical approaches to address this question. Colon and breast cancer cells were identified where CAV1 levels were low due to epigenetic suppression and could be reverted by treatment with the methyltransferase inhibitor 5’-azacytidine. Exposure of these cells to anti-neoplastic drugs for short periods of time (24-48 h) increased CAV1 expression through ROS production and MEK/ERK activation. In colon cancer cells, increased CAV1 expression enhanced migration and invasion in vitro via pathways requiring Src-family kinases, as well as Rac-1 activity. Finally, elevated CAV1 expression in colon cancer cells following exposure in vitro to sub-cytotoxic drug concentrations increased their metastatic potential in vivo. Therefore exposure of cancer cells to anti-neoplastic drugs at non-lethal drug concentrations induces signaling events and changes in transcription that favor CAV1-dependent migration, invasion and metastasis. Importantly, this may occur in the absence of selection for drug-resistance.
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Affiliation(s)
- Natalia I Díaz-Valdivia
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Claudia C Calderón
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Jorge E Díaz
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Lorena Lobos-González
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Fundación Ciencia & Vida, Santiago, Chile
| | - Hugo Sepulveda
- Gene Regulation Laboratory, Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andrés Bello, Santiago, Chile
| | - Rina J Ortíz
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Universidad Bernardo O Higgins, Facultad de Salud, Departamento de Ciencias Químicas y Biológicas, Santiago, Chile
| | - Samuel Martinez
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | | | - Horacio J Maldonado
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Patricio Silva
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Sergio Wehinger
- Faculty of Health Sciences, University of Talca, Interdisciplinary Excellence Research Program Healthy Ageing (PIEI-ES), Talca, Chile
| | - Verónica A Burzio
- Fundación Ciencia & Vida, Santiago, Chile.,Faculty of Biological Sciences, Universidad Andrés Bello, Santiago, Chile
| | - Vicente A Torres
- Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Martín Montecino
- Gene Regulation Laboratory, Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andrés Bello, Santiago, Chile
| | - Lisette Leyton
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Andrew F G Quest
- Cellular Communication Laboratory, Center for Molecular Studies of the Cell (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
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24
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Cui Y, Zhu T, Song X, Liu J, Liu S, Zhao R. Downregulation of caveolin-1 increased EGFR-TKIs sensitivity in lung adenocarcinoma cell line with EGFR mutation. Biochem Biophys Res Commun 2017; 495:733-739. [PMID: 29137977 DOI: 10.1016/j.bbrc.2017.11.075] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 11/10/2017] [Indexed: 12/21/2022]
Abstract
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have shown notable effects in lung adenocarcinoma patients harboring EGFR mutations, there are significant differences between individual patients in the degree of benefits provided by EGFR-TKIs. Some evidence supports a role for caveolin-1 (Cav-1) in modulating drug sensitivity. This study aimed to investigate whether Cav-1 plays an important role in sensitivity to EGFR-TKIs in lung adenocarcinoma cells. Downregulation of Cav-1 in PC-9 cells were performed to investigate changes in sensitivity to EGFR-TKIs in vitro and in vivo. Knockdown of Cav-1 dramatically enhanced sensitivity to EGFR-TKIs by down-regulating phosphorylation of EGFR. These results suggest that Cav-1 may be a predictor of the poor efficacy of EGFR-TKIs treatment in lung adenocarcinoma with EGFR mutations.
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Affiliation(s)
- Yujie Cui
- Department of Oncology, Hebei Medical University, Shijiazhuang 050017, Hebei, China; Department of Oncology, Hebei Genenral Hospital, Shijiazhuang 050051, Hebei, China
| | - Tienian Zhu
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang 050017, Hebei, China; Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, Hebei, China.
| | - Xuejing Song
- Department of Oncology, The First Hospital of Shijiazhuang, 050011 Hebei, China
| | - Jiankun Liu
- Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang 050082, Hebei, China
| | - Shuang Liu
- Department of Pathology, Bethune International Peace Hospital, Shijiazhuang 050082, Hebei, China
| | - Ruijing Zhao
- Department of Immunology, Hebei Medical University, Key Laboratory of Immune Mechanism and Intervention on Serious Disease in Hebei Province, Shijiazhuang 050017, Hebei, China.
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25
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Li L, Zhang K, Lu C, Sun Q, Zhao S, Jiao L, Han R, Lin C, Jiang J, Zhao M, He Y. Caveolin-1-mediated STAT3 activation determines electrotaxis of human lung cancer cells. Oncotarget 2017; 8:95741-95754. [PMID: 29221162 PMCID: PMC5707056 DOI: 10.18632/oncotarget.21306] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 08/26/2017] [Indexed: 12/28/2022] Open
Abstract
Migration of cancer cells leads to the invasion of distant organs by primary tumors. Further, endogenous electric fields (EFs) in the tumor microenvironment direct the migration of lung cancer cells by a process referred to as electrotaxis – although the precise mechanism remains unclear. Caveolin-1 (Cav-1) is a multifunctional scaffolding protein that is associated with directional cell migration and lung cancer invasion; however, its precise role in lung cancer electrotaxis is unknown. In the present study, we first detected outward electric currents on the tumor body surface in lung cancer xenografts using a highly-sensitive vibrating probe. Next, we found that highly-metastatic H1650-M3 cells migrated directionally to the cathode. In addition, reversal of the EF polarity reversed the direction of migration. Mechanistically, EFs activated Cav-1 and the downstream signaling molecule STAT3. RNA interference of Cav-1 reduced directional cell migration, which was accompanied by dampened STAT3 activation. Furthermore, pharmacological inhibition of STAT3 significantly reduced the electrotactic response, while rescue of STAT3 activation in Cav-1 knock-down cells restored electrotaxis. Taken together, these results suggest that endogenous EFs in the tumor micro-environment might play an important role in lung cancer metastasis by guiding cell migration through a Cav-1/STAT3-mediated signaling pathway.
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Affiliation(s)
- Li Li
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Kejun Zhang
- Department of Clinical Laboratory, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Conghua Lu
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Qin Sun
- School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Sanjun Zhao
- School of Life Sciences, Yunnan Normal University, Kunming 650500, China
| | - Lin Jiao
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Rui Han
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Caiyu Lin
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Jianxin Jiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Min Zhao
- Department of Dermatology, Institute for Regenerative Cures, University of California, Davis, CA 95817, USA
| | - Yong He
- Department of Respiratory Disease, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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26
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Chatterjee M, Ben-Josef E, Robb R, Vedaie M, Seum S, Thirumoorthy K, Palanichamy K, Harbrecht M, Chakravarti A, Williams TM. Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy. Cancer Res 2017; 77:5925-5937. [PMID: 28923854 DOI: 10.1158/0008-5472.can-17-0604] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 07/03/2017] [Accepted: 09/06/2017] [Indexed: 01/04/2023]
Abstract
Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for transendothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above that respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells, where Cav-1 was attenuated, exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs. Cancer Res; 77(21); 5925-37. ©2017 AACR.
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Affiliation(s)
- Moumita Chatterjee
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Edgar Ben-Josef
- Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ryan Robb
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Marall Vedaie
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Star Seum
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Krishnan Thirumoorthy
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Kamalakannan Palanichamy
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Matthew Harbrecht
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Arnab Chakravarti
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Terence M Williams
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio.
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27
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Cheng B, Lin M, Li Y, Huang G, Yang H, Genin GM, Deshpande VS, Lu TJ, Xu F. An Integrated Stochastic Model of Matrix-Stiffness-Dependent Filopodial Dynamics. Biophys J 2017; 111:2051-2061. [PMID: 27806285 DOI: 10.1016/j.bpj.2016.09.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 09/18/2016] [Accepted: 09/19/2016] [Indexed: 11/25/2022] Open
Abstract
The ways that living cells regulate their behavior in response to their local mechanical environment underlie growth, development, and healing and are important to critical pathologies such as metastasis and fibrosis. Although extensive experimental evidence supports the hypothesis that this regulation is governed by the dependence of filopodial dynamics upon extracellular matrix stiffness, the pathways for this dependence are unclear. We therefore developed a model to relate filopodial focal adhesion dynamics to integrin-mediated Rho signaling kinetics. Results showed that focal adhesion maturation, i.e., focal adhesion links reinforcement and integrin clustering, dominates over filopodial dynamics. Downregulated focal adhesion maturation leads to the biphasic relationship between extracellular matrix stiffness and retrograde flow that has been observed in embryonic chick forebrain neurons, whereas upregulated maturation leads to the monotonically decreasing relationship that has been observed in mouse embryonic fibroblasts. When integrin-mediated Rho activation and stress-dependent focal adhesion maturation are combined, the model shows how filopodial dynamics endows cells with exquisite mechanosensing. Taken together, the results support the hypothesis that mechanical and structural factors combine with signaling kinetics to enable cells to probe their environments via filopodial dynamics.
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Affiliation(s)
- Bo Cheng
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Min Lin
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Yuhui Li
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Guoyou Huang
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Hui Yang
- School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Guy M Genin
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Vikram S Deshpande
- Department of Engineering, University of Cambridge, Cambridge, United Kingdom
| | - Tian Jian Lu
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Feng Xu
- The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China.
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28
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Lui AJ, Geanes ES, Ogony J, Behbod F, Marquess J, Valdez K, Jewell W, Tawfik O, Lewis-Wambi J. IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. Cancer Lett 2017; 399:29-43. [PMID: 28411130 DOI: 10.1016/j.canlet.2017.04.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 03/23/2017] [Accepted: 04/04/2017] [Indexed: 12/19/2022]
Abstract
Interferon induced transmembrane protein 1 (IFITM1) belongs to a family of interferon stimulated genes (ISGs) that is associated with tumor progression and DNA damage resistance; however, its role in endocrine resistance is not known. Here, we correlate IFITM1 expression with clinical stage and poor response to endocrine therapy in a tissue microarray consisting of 94 estrogen receptor (ER)-positive breast tumors. IFITM1 overexpression is confirmed in the AI-resistant MCF-7:5C cell line and not found in AI-sensitive MCF-7 cells. In this study, the orthotopic (mammary fat pad) and mouse mammary intraductal (MIND) models of breast cancer are used to assess tumor growth and invasion in vivo. Lentivirus-mediated shRNA knockdown of IFITM1 in AI-resistant MCF-7:5C cells diminished tumor growth and invasion and induced cell death, whereas overexpression of IFITM1 in wild-type MCF-7 cells promoted estrogen-independent growth and enhanced their aggressive phenotype. Mechanistic studies indicated that loss of IFITM1 in MCF-7:5C cells markedly increased p21 transcription, expression and nuclear localization which was mediated by JAK/STAT activation. These findings suggest IFITM1 overexpression contributes to breast cancer progression and that targeting IFITM1 may be therapeutically beneficial to patients with endocrine-resistant disease.
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Affiliation(s)
- Asona J Lui
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Eric S Geanes
- Department of Cancer Biology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Joshua Ogony
- Department of Cancer Biology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Fariba Behbod
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Jordan Marquess
- University of Kansas Medical Center School of Medicine, USA.
| | - Kelli Valdez
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - William Jewell
- The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
| | - Ossama Tawfik
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, USA.
| | - Joan Lewis-Wambi
- Department of Cancer Biology, University of Kansas Medical Center, USA; The University of Kansas Cancer Center, Kansas City, KS 66160, USA.
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The metastatic suppressor NDRG1 inhibits EMT, migration and invasion through interaction and promotion of caveolin-1 ubiquitylation in human colorectal cancer cells. Oncogene 2017; 36:4323-4335. [PMID: 28346422 PMCID: PMC5537633 DOI: 10.1038/onc.2017.74] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 01/15/2017] [Accepted: 02/14/2017] [Indexed: 02/07/2023]
Abstract
N-myc downstream-regulated gene 1 (NDRG1) has been reported to act as a key regulatory molecule in tumor progression-related signaling pathways, especially in tumor metastasis. However, the related mechanism has not been fully discovered yet. Herein we demonstrated that the novel molecule of cell migration and invasion, caveolin-1, has direct interaction with NDRG1 in human colorectal cancer (CRC) cells. Moreover, we discovered that NDRG1 reduces caveolin-1 protein expression through promoting its ubiquitylation and subsequent degradation via the proteasome in CRC cells. In addition, caveolin-1 mediates the suppressive function of NDRG1 in epithelial–mesenchymal transition, migration and invasion in vitro and metastasis in vivo. These results help to fulfill the potential mechanisms of NDRG1 in anti-metastatic treatment for human colorectal cancer.
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Mohammed DA, Helal DS. Prognostic significance of epithelial/stromal caveolin‐1 expression in prostatic hyperplasia, high grade prostatic intraepithelial hyperplasia and prostatic carcinoma and its correlation with microvessel density. J Egypt Natl Canc Inst 2017; 29:25-31. [DOI: 10.1016/j.jnci.2017.01.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 01/02/2017] [Accepted: 01/10/2017] [Indexed: 12/16/2022] Open
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Fu P, Chen F, Pan Q, Zhao X, Zhao C, Cho WCS, Chen H. The different functions and clinical significances of caveolin-1 in human adenocarcinoma and squamous cell carcinoma. Onco Targets Ther 2017; 10:819-835. [PMID: 28243118 PMCID: PMC5317307 DOI: 10.2147/ott.s123912] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Caveolin-1 (Cav-1), a major structural protein of caveolae, is an integral membrane protein which plays an important role in the progression of carcinoma. However, whether Cav-1 acts as a tumor promoter or a tumor suppressor still remains controversial. For example, the tumor-promoting function of Cav-1 has been found in renal cancer, prostate cancer, tongue squamous cell carcinoma (SCC), lung SCC and bladder SCC. In contrast, Cav-1 also plays an inhibitory role in esophagus adenocarcinoma, lung adenocarcinoma and cutaneous SCC. The role of Cav-1 is still controversial in thyroid cancer, hepatocellular carcinoma, gastric adenocarcinoma, colon adenocarcinoma, breast cancer, pancreas cancer, oral SCC, laryngeal SCC, head and neck SCC, esophageal SCC and cervical SCC. Besides, it has been reported that the loss of stromal Cav-1 might predict poor prognosis in breast cancer, gastric cancer, pancreas cancer, prostate cancer, oral SCC and esophageal SCC. However, the accumulation of stromal Cav-1 has been found to be promoted by the progression of tongue SCC. Taken together, Cav-1 seems playing a different role in different cancer subtypes even of the same organ, as well as acting differently in the same cancer subtype of different organs. Thus, we hereby explore the functions of Cav-1 in human adenocarcinoma and SCC from the perspective of clinical significances and pathogenesis. We envision that novel targets may come with the further investigation of Cav-1 in carcinogenesis.
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Affiliation(s)
- Pin Fu
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan
| | - Fuchun Chen
- Department of Thoracosurgery, Traditional Chinese Medical Hospital of Wenling, Wenling, Zhejiang
| | - Qi Pan
- Department of Thoracosurgery, Traditional Chinese Medical Hospital of Wenling, Wenling, Zhejiang
| | - Xianda Zhao
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan
| | - Chen Zhao
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan
| | | | - Honglei Chen
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan; Department of Pathology, Maternal and Child Health Hospital of Hubei, Wuhan, People's Republic of China
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Demirci NS, Dogan M, Erdem GU, Kacar S, Turhan T, Kilickap S, Cigirgan LC, Kayacetin E, Bozkaya Y, Zengin N. Is plasma caveolin-1 level a prognostic biomarker in metastatic pancreatic cancer? Saudi J Gastroenterol 2017; 23:183-189. [PMID: 28611342 PMCID: PMC5470378 DOI: 10.4103/sjg.sjg_483_16] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIMS To evaluate the prognostic significance of plasma caveolin (CAV)-1 and its association with survival and treatment response rates in metastatic pancreatic cancer (MPC). PATIENTS AND METHODS Plasma samples were prospectively collected from 41 patients with newly diagnosed MPC. Moreover, plasma samples were collected from 48 patients with chronic pancreatitis and 41 healthy individuals (control groups) for assessing Cav-1 levels. Plasma Cav-1 levels were evaluated at baseline and after three cycles of chemotherapy in the patients with MPC. RESULTS The median Cav-1 level was 13.8 ng/mL for the patients with MPC and 12.2 ng/mL for healthy individuals (P = 0.009). The Cav-1 cut-off level was calculated as 11.6 ng/mL by using the receiver operating characteristic curve. The median overall survival and progression-free survival rates were 5 and 2.4 months, respectively, for participants with a high basal plasma Cav-1 level; the corresponding values were 10.5 and 9.4 months for participants with a low plasma Cav-1 level (P = 0.011 and P= 0.003, respectively). Of the 41 patients with MPC, 23 completed at least three cycles of chemotherapy. The median Cav-1 level was 13 ng/mL for post-treatment MPC (r2: 0.917; P= 0.001). High basal plasma caveolin-1 level have continued to remain at high levels even after chemotherapy, showing a trend toward worse response rates (P = 0.086). CONCLUSION High basal plasma Cav-1 levels seem to be associated with poor survival and tend to yield worse therapeutic outcomes in patients with MPC. This study is the first to evaluate the prognostic significance of plasma Cav-1 levels as a prognostic factor in patients with MPC. However, larger prospective clinical trials are warranted.
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Affiliation(s)
- Nebi S. Demirci
- Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey,Address for correspondence: Dr. Nebi S. Demirci, Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey. E-mail:
| | - Mutlu Dogan
- Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Gokmen U. Erdem
- Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Sabite Kacar
- Department of Gastroenterology, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey
| | - Turan Turhan
- Department of Biochemistry, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Saadettin Kilickap
- Department of Medical Oncology, Hacettepe University Medical Faculty, Ankara, Turkey
| | - Lutfi C. Cigirgan
- Department of Biochemistry, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Ertugrul Kayacetin
- Department of Gastroenterology, Turkiye Yuksek Ihtisas Training and Research Hospital, Ankara, Turkey
| | - Yakup Bozkaya
- Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Nurullah Zengin
- Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
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Wang Z, Wang N, Liu P, Peng F, Tang H, Chen Q, Xu R, Dai Y, Lin Y, Xie X, Peng C, Situ H. Caveolin-1, a stress-related oncotarget, in drug resistance. Oncotarget 2016; 6:37135-50. [PMID: 26431273 PMCID: PMC4741920 DOI: 10.18632/oncotarget.5789] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 09/08/2015] [Indexed: 12/28/2022] Open
Abstract
Caveolin-1 (Cav-1) is both a tumor suppressor and an oncoprotein. Cav-1 overexpression was frequently confirmed in advanced cancer stages and positively associated with ABC transporters, cancer stem cell populations, aerobic glycolysis activity and autophagy. Cav-1 was tied to various stresses including radiotherapy, fluid shear and oxidative stresses and ultraviolet exposure, and interacted with stress signals such as AMP-activated protein kinase. Finally, a Cav-1 fluctuation model during cancer development is provided and Cav-1 is suggested to be a stress signal and cytoprotective. Loss of Cav-1 may increase susceptibility to oncogenic events. However, research to explore the underlying molecular network between Cav-1 and stress signals is warranted.
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Affiliation(s)
- Zhiyu Wang
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Neng Wang
- Department of Breast Oncology, Sun Yat-sen Univeristy Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Pengxi Liu
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fu Peng
- Pharmacy College, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Guangzhou, China
| | - Hailin Tang
- Department of Breast Oncology, Sun Yat-sen Univeristy Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Qianjun Chen
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rui Xu
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yan Dai
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Lin
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoming Xie
- Department of Breast Oncology, Sun Yat-sen Univeristy Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
| | - Cheng Peng
- Pharmacy College, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Guangzhou, China
| | - Honglin Situ
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine, Guangzhou, China
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Jin X, Liu X, Li X, Guan Y. Integrated Analysis of DNA Methylation and mRNA Expression Profiles Data to Identify Key Genes in Lung Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4369431. [PMID: 27610375 PMCID: PMC5005524 DOI: 10.1155/2016/4369431] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 06/21/2016] [Accepted: 06/21/2016] [Indexed: 11/17/2022]
Abstract
Introduction. Lung adenocarcinoma (LAC) is the most frequent type of lung cancer and has a high metastatic rate at an early stage. This study is aimed at identifying LAC-associated genes. Materials and Methods. GSE62950 downloaded from Gene Expression Omnibus included a DNA methylation dataset and an mRNA expression profiles dataset, both of which included 28 LAC tissue samples and 28 adjacent normal tissue samples. The differentially expressed genes (DEGs) were screened by Limma package in R, and their functions were predicted by enrichment analysis using TargetMine online tool. Then, protein-protein interaction (PPI) network was constructed using STRING and Cytoscape. Finally, LAC-associated methylation sites were identified by CpGassoc package in R and mapped to the DEGs to obtain LAC-associated DEGs. Results. Total 913 DEGs were identified in LAC tissues. In the PPI networks, MAD2L1, AURKB, CCNB2, CDC20, and WNT3A had higher degrees, and the first four genes might be involved in LAC through interaction. Total 8856 LAC-associated methylation sites were identified and mapped to the DEGs. And there were 29 LAC-associated methylation sites located in 27 DEGs (e.g., SH3GL2, BAI3, CDH13, JAM2, MT1A, LHX6, and IGFBP3). Conclusions. These key genes might play a role in pathogenesis of LAC.
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Affiliation(s)
- Xiang Jin
- Department of Respiration, The First Hospital of Jilin University, Changchun 130021, China
| | - Xingang Liu
- ICU Department, The First Hospital of Jilin University, Changchun 130021, China
| | - Xiaodan Li
- Department of Respiration, The First Hospital of Jilin University, Changchun 130021, China
| | - Yinghui Guan
- Department of Respiration, The First Hospital of Jilin University, Changchun 130021, China
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Unahabhokha T, Chanvorachote P, Pongrakhananon V. The attenuation of epithelial to mesenchymal transition and induction of anoikis by gigantol in human lung cancer H460 cells. Tumour Biol 2016; 37:8633-41. [PMID: 26733180 DOI: 10.1007/s13277-015-4717-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 12/21/2015] [Indexed: 12/21/2022] Open
Abstract
Lung cancer has been the major cause of death within patients due to the high metastatic rate. One of the most essential processes of metastasis is the ability of cancer cells to resist the programmed cell death in a detached condition called anoikis. The discoveries of new natural compound that is able to sensitize anoikis in cancer cells have garnered the most interest in cancer pharmaceutical science. Gigantol, a bibenzyl compound extracted from Dendrobium draconis, has been a promising natural derived compound for cancer therapy due to several cytotoxic effects in cancer cells. This study has demonstrated for the first time that gigantol significantly decreases lung cancer cells' viability in a detached condition through anoikis and anchorage-independent assays. Western blotting analysis reveals that gigantol greatly decreases epithelial to mesenchymal transition (EMT) markers including N-cadherin, vimentin, and Slug leading to a significant suppression of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and caveolin-1 (cav-1) survival pathways during the detached condition. Therefore, gigantol could be a potential cancer therapeutic compound suggesting for further development for cancer therapy.
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Affiliation(s)
- Thitita Unahabhokha
- Pharmaceutical Technology (International) Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand, 10330
- Cell-Based Drug and Health Product Development Research Unit, Chulalongkorn University, Bangkok, Thailand, 10330
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand, 10330
- Cell-Based Drug and Health Product Development Research Unit, Chulalongkorn University, Bangkok, Thailand, 10330
| | - Varisa Pongrakhananon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand, 10330.
- Cell-Based Drug and Health Product Development Research Unit, Chulalongkorn University, Bangkok, Thailand, 10330.
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ROR1 sustains caveolae and survival signalling as a scaffold of cavin-1 and caveolin-1. Nat Commun 2016; 7:10060. [PMID: 26725982 PMCID: PMC4777216 DOI: 10.1038/ncomms10060] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 10/28/2015] [Indexed: 01/03/2023] Open
Abstract
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) sustains prosurvival signalling directly downstream of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinoma. Here we report an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. This kinase-independent function of ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane, thereby preventing the lysosomal degradation of CAV1. Caveolae structures and prosurvival signalling towards AKT through multiple RTKs are consequently sustained. These findings provide mechanistic insight into how ROR1 inhibition can overcome EGFR-tyrosine kinase inhibitor (TKI) resistance due to bypass signalling via diverse RTKs such as MET and IGF-IR, which is currently a major clinical obstacle. Considering its onco-embryonic expression, inhibition of the scaffold function of ROR1 in patients with lung adenocarcinoma is an attractive approach for improved treatment of this devastating cancer.
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37
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Liu JM, Cheng SH, Liu XX, Xia C, Wang WW, Ma XL. Prognostic value of caveolin-1 in genitourinary cancer: a meta-analysis. Int J Clin Exp Med 2015; 8:20760-20768. [PMID: 26884999 PMCID: PMC4723844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 10/25/2015] [Indexed: 06/05/2023]
Abstract
We aimed to obtain the most comprehensive picture to date of the prognostic value of caveolin-1 (Cav-1) in genitourinary carcinoma by meta-analyzing all eligible studies in PubMed and EMBASE. Data on patient clinical characteristics, cancer-specific survival (CSS) and recurrence-free survival (RFS) were extracted. The meta-analysis included 6 articles on prostate cancer, 5 on renal cancer, 1 on bladder cancer and 1 on transition cell carcinoma of the upper urinary tract. Two studies examining the association of ELISA-measured Cav-1 levels in serum with RFS in 621 patients with prostate cancer gave a combined hazard ratio (HR) of 1.25 (95% CI 0.36 to 4.36). The other 4 studies on prostate cancer examined the association of immunohistochemically determined Cav-1 levels in cancerous tissue with RFS and gave a combined HR of 1.83 (95% CI 1.36 to 2.47). Three studies on renal cancer examining the association of Cav-1 levels with CSS gave a multivariate HR of 1.98 (95% CI 1.35 to 2.90). The single studies on bladder carcinoma and upper urinary tract carcinoma gave, respectively, a multivariate HR of 2.28 (95% CI 1.09 to 4.74) for the relationship of Cav-1 levels to DFS, and a multivariate HR of 5.08 (95% CI 1.799 to 14.342) for the relationship of Cav-1 levels to CSS. This meta-analysis of available evidence suggests that elevated Cav-1 levels in serum can predict poor survival in patients with genitourinary cancer, which may help identify high-risk patients earlier and guide clinical decision-making.
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Affiliation(s)
- Jia-Ming Liu
- Department of Urology, West China Hospital, Sichuan UniversityGuoxuexiang 37, Chengdu 610041, Sichuan, China
| | - Si-Hang Cheng
- Department of Urology, West China Hospital, Sichuan UniversityGuoxuexiang 37, Chengdu 610041, Sichuan, China
| | - Xiao-Xiao Liu
- West China School of Medicine, Sichuan UniversityGuoxuexiang 37, Chengdu 610041, Sichuan, China
| | - Chao Xia
- West China School of Medicine, Sichuan UniversityGuoxuexiang 37, Chengdu 610041, Sichuan, China
| | - Wei-Wen Wang
- West China School of Medicine, Sichuan UniversityGuoxuexiang 37, Chengdu 610041, Sichuan, China
| | - Xue-Lei Ma
- Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityChengdu 610041, China
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38
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Duregon E, Senetta R, Pittaro A, Verdun di Cantogno L, Stella G, De Blasi P, Zorzetto M, Mantovani C, Papotti M, Cassoni P. CAVEOLIN-1 expression in brain metastasis from lung cancer predicts worse outcome and radioresistance, irrespective of tumor histotype. Oncotarget 2015; 6:29626-36. [PMID: 26315660 PMCID: PMC4745751 DOI: 10.18632/oncotarget.4988] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 07/16/2015] [Indexed: 02/02/2023] Open
Abstract
Brain metastases develop in one-third of patients with non-small-cell lung cancer and are associated with a dismal prognosis, irrespective of surgery or chemo-radiotherapy. Pathological markers for predicting outcomes after surgical resection and radiotherapy responsiveness are still lacking. Caveolin 1 has been associated with chemo- and radioresistance in various tumors, including non-small-cell lung cancer. Here, caveolin 1 expression was assessed in a series of 69 brain metastases from non-small-cell lung cancer and matched primary tumors to determine its role in predicting survival and radiotherapy responsiveness. Only caveolin 1 expression in brain metastasis was associated with poor prognosis and an increased risk of death (log rank test, p = 0.015). Moreover, in the younger patients (median age of <54 years), caveolin 1 expression neutralized the favorable effect of young age on survival compared with the older patients. Among the radiotherapy-treated patients, an increased risk of death was detected in the group with caveolin 1-positive brain metastasis (14 out of 22 patients, HR=6.839, 95% CI 1.849 to 25.301, Wald test p = 0.004). Overall, caveolin 1 expression in brain metastasis from non-small-cell lung cancer is independently predictive of worse outcome and radioresistance and could become an additional tool for personalized therapy in the critical subset of brain-metastatic non-small-cell lung cancer patients.
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Affiliation(s)
- Eleonora Duregon
- Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Turin, Italy
| | | | | | | | - Giulia Stella
- Laboratory of Biochemistry and Genetics, Pneumology Unit, Department of Molecular Medicine University and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Michele Zorzetto
- Laboratory of Biochemistry and Genetics, Pneumology Unit, Department of Molecular Medicine University and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Mauro Papotti
- Department of Oncology, University of Torino at San Luigi Hospital, Orbassano, Turin, Italy
| | - Paola Cassoni
- Department of Medical Sciences, University of Torino, Italy
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Busaranon K, Plaimee P, Sritularak B, Chanvorachote P. Moscatilin inhibits epithelial-to-mesenchymal transition and sensitizes anoikis in human lung cancer H460 cells. J Nat Med 2015; 70:18-27. [PMID: 26384689 DOI: 10.1007/s11418-015-0931-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 07/21/2015] [Indexed: 12/18/2022]
Abstract
Metastasis in lung cancer has been recognized as an important cause of high mortality. Resistance to anoikis and the epithelial-to-mesenchymal transition (EMT) are critical factors for the successful spread of cancer cells. Compounds that suppress these features of cancer cells should be potentially active for anti-metastasis approaches. We have demonstrated for the first time that moscatilin, at its non-toxic concentrations to lung cancer cells and human normal keratinocytes, significantly decreases lung cancer cell survival in the detached condition, and suppresses the formation of tumors in an anchorage-independent growth assay. Furthermore, we found that moscatilin significantly decreased the activated level of survival proteins, namely ERK and Akt. In addition, moscatilin down-regulated cavelolin-1 (Cav-1), leading to a reduction in anti-apoptotic Mcl-1 protein. In terms of EMT, treatment of the cells with moscatilin significantly suppressed mesenchymal cell markers, namely vimentin, Slug, and Snail. These results indicate that moscatilin inhibited anoikis resistance in lung cancer cells via survival suppression, Cav-1 down-regulation, and inhibition of EMT. The compound could therefore be beneficial for the treatment and prevention of lung cancer metastasis.
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Affiliation(s)
- Kesarin Busaranon
- Faculty of Pharmacy, Rangsit University, Pathum Thani, 12000, Thailand
| | - Preeyaporn Plaimee
- Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Boonchoo Sritularak
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Pithi Chanvorachote
- Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand. .,Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
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Caiola E, Marrazzo E, Alesci S, Broggini M, Marabese M. ∆Np73beta induces caveolin-1 in human non-small cell lung cancer cell line H1299. Tumour Biol 2015; 37:2015-21. [PMID: 26337278 DOI: 10.1007/s13277-015-4012-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 08/27/2015] [Indexed: 11/26/2022] Open
Abstract
Caveolins have recently attracted attention for their possible involvement in signal transduction. Their role in cancer is debated, being reported both a suppressive and oncogenic role in different experimental conditions. Caveolin-1 is regulated by the tumor suppressor p53 which is able to bind its promoter and activate transcription. We had previous evidences indicating that a specific p73 isoform, namely ∆Np73β, when overexpressed in NCI-H1299 induced growth arrest and cell death. By gene expression analysis in cell transiently overexpressed with ∆Np73β, a strong induction of caveolin-1 was found. Caveolin was induced both at mRNA and protein level, and we characterised the promoter sequence of the gene encoding for caveolin-1 and found that the promoter region containing the putative p53 (and hence p73) binding sequence was responsive to ∆Np73β, but not to ∆Np73α and ∆Np73γ which do not induce growth arrest as ∆Np73β does. A reduction in cell adhesion was observed in ∆Np73β overexpressing cells, again supporting a possible role of caveolins in determining these effects. By using specific siRNA directed against human caveolin-1, we could not however antagonize the effects induced by ∆Np73β. Although caveolin-1 represents one of the genes whose expression is strongly activated by ∆Np73β, we could not define a role of caveolin-1 as a mediator of ∆Np73β associated growth arrest. It could well be that the expression of caveolin-1 is able to mediate other activities of ∆Np73β, and studies are in progress to determine whether its expression is mainly associated to metastatic spread.
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Affiliation(s)
- Elisa Caiola
- Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via G. La Masa 19, 20156, Milan, Italy
| | - Eleonora Marrazzo
- Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via G. La Masa 19, 20156, Milan, Italy
| | - Simona Alesci
- Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via G. La Masa 19, 20156, Milan, Italy
| | - Massimo Broggini
- Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via G. La Masa 19, 20156, Milan, Italy.
| | - Mirko Marabese
- Laboratory of Molecular Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via G. La Masa 19, 20156, Milan, Italy
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Han F, Zhang L, Zhou Y, Yi X. Caveolin-1 regulates cell apoptosis and invasion ability in paclitaxel-induced multidrug-resistant A549 lung cancer cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:8937-8947. [PMID: 26464635 PMCID: PMC4583867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 07/29/2015] [Indexed: 06/05/2023]
Abstract
The aim of the study was to investigate the effect and potential mechanism of caveolin-1 (Cav1) knockdown in paclitaxel-resistant lung cancer A549/Taxol cells. The human paclitaxel-resistant lung cancer cell line A549/Taxol was transfected with a Cav1 shRNA lentiviral vector. Interference efficiency for Cav1 was detected by real-time PCR and Western blotting. A MTT assay was used to determine cell proliferation, and flow cytometry was used to detect the cell cycle stage and apoptosis. Cell migration and invasion capability were detected by a transwell assay. Protein levels of related signaling molecules were detected by Western blotting. We successfully constructed a stable A549/Taxol cell line expressing low levels of Cav1. Cav1 knockdown significantly inhibited cell proliferation and induced G0/G1 arrest and cell apoptosis in vitro and in vivo. In addition, these effects correlated significantly with a reduction in cyclin D1 expression and activation of the Bcl-2/Bax-mediated mitochondrial apoptosis pathway. Furthermore, knockdown of Cav1 inhibited cell migration and invasion, and this may be related to the inhibition of AKT and the subsequent decreased protein expression of MMP2, MMP7 and MMP9.
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Affiliation(s)
- Fei Han
- Department of Pathology, Shanghai Tongji Hospital Affiliated to Shanghai Tongji UniversityShanghai 200065, China
- Department of Pathology, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong UniversityShanghai 200030, China
| | - Long Zhang
- Department of Pathology, Shanghai Tongji Hospital Affiliated to Shanghai Tongji UniversityShanghai 200065, China
| | - Yongxin Zhou
- Department of Thoracic-Cardiovascular Surgery, Tongji Hospital of Tongji University389 Xincun Rd, Shanghai, China
| | - Xianghua Yi
- Department of Pathology, Shanghai Tongji Hospital Affiliated to Shanghai Tongji UniversityShanghai 200065, China
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Luan TY, Zhu TN, Cui YJ, Zhang G, Song XJ, Gao DM, Zhang YM, Zhao QL, Liu S, Su TY, Zhao RJ. Expression of caveolin-1 is correlated with lung adenocarcinoma proliferation, migration, and invasion. Med Oncol 2015; 32:207. [PMID: 26094077 DOI: 10.1007/s12032-015-0644-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 05/20/2015] [Indexed: 02/05/2023]
Abstract
Both tumor suppressor and tumor promoter roles, which are dependent on the tumor type, have been described for caveolin-1 (CAV-1). Because CAV-1 can modulate cell signaling, we tested the hypothesis that it regulates lung adenocarcinoma cell proliferation and metastasis via modulation of epidermal growth factor receptor (EGFR) activity. The lung adenocarcinoma cell line, GLC-82, was transfected with pcDNA3.1CAV-1 plasmid, before cell proliferation, migration, and invasion were analyzed. In the in vivo xenograft model, the relationship between the CAV-1 expression and EGFR phosphorylation and signaling was assessed by western blot analysis. The relationship between the CAV-1 as well as Ki67 expression and the clinicopathological characteristics of 68 lung adenocarcinoma patients was also examined using immunohistochemistry. Overexpression of CAV-1 significantly increased GLC-82 proliferation (p < 0.001), migration (p < 0.001), and invasion (p = 0.002) as well as EGFR and ERK phosphorylation (p < 0.05). The GLC-82/CAV-1 cell tumors were also significantly larger than those of control cells (all p ≤ 0.05). In lung adenocarcinoma patients, CAV-1 expression was positively correlated with lymph node metastasis and cancer stage. Finally, CAV-1 expression was associated with the expression of Ki-67, a marker of cell proliferation. CAV-1 enhanced GLC-82 cell proliferation, migration, and invasion possibly through EGFR and ERK signaling. Furthermore, the relationship of CAV-1 with Ki67 expression, a marker of proliferative capacity, in lung adenocarcinoma samples is suggestive of its role in disease progression. Further studies are required to confirm the role of CAV-1 in the metastasis of lung adenocarcinoma as well as its potential prognostic and therapeutic value.
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Affiliation(s)
- Tian-Yan Luan
- Department of Oncology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China
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Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis. Oncotarget 2015; 5:3541-54. [PMID: 24939878 PMCID: PMC4116501 DOI: 10.18632/oncotarget.1956] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Cancer stem cells (CSCs) may represent targets for carcinogenic initiation by chemical and environmental agents. Recent studies have raised a concern over the potential carcinogenicity of carbon nanotubes (CNTs), one of the most commonly used engineered nanomaterials with asbestos-like properties. Here, we show that chronic (6-month) exposure of human lung epithelial cells to single-walled (SW) CNTs at the workplace-relevant concentration induced an emergence of lung CSCs, as indicated by the induction of CSC tumor spheres and side population (SP). These CSCs, which were found to overexpress tumor promoter caveolin-1 (Cav-1), displayed aggressive cancer phenotypes of apoptosis resistance and enhanced cell invasion and migration compared with their non-CSC counterpart. Using gene manipulation strategies, we reveal for the first time that Cav-1 plays an essential role in CSC regulation and aggressiveness of SWCNT-transformed cells partly through p53 dysregulation, consistent with their suggested role by microarray and gene ontology analysis. Cav-1 not only promoted tumorigenesis in a xenograft mouse model but also metastasis of the transformed cells to neighboring tissues. Since CSCs are crucial to the initiation and early development of carcinogenesis, our findings on CSC induction by SWCNTs and Cav-1 could aid in the early detection and risk assessment of the disease.
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Weiss CR, Guan Q, Ma Y, Qing G, Bernstein CN, Warrington RJ, Peng Z. The potential protective role of caveolin-1 in intestinal inflammation in TNBS-induced murine colitis. PLoS One 2015; 10:e0119004. [PMID: 25756273 PMCID: PMC4355071 DOI: 10.1371/journal.pone.0119004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 01/19/2015] [Indexed: 12/19/2022] Open
Abstract
Background Caveolin-1 (Cav-1) is a multifunctional scaffolding protein serving as a platform for the cell’s signal-transduction and playing an important role in inflammation. However, its role in inflammatory bowel disease is not clear. A recent study showed that Cav-1 is increased and mediates angiogenesis in dextran sodium sulphate-induced colitis, which are contradictory to our pilot findings in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. In the present study, we further clarified the role of Cav-1 in TNBS-induced colitis. Methods In BALB/c mice, acute colitis was induced by intra-rectal administration of one dose TNBS, while chronic colitis was induced by administration of TNBS once a week for 7 weeks. To assess the effects of complete loss of Cav-1, Cav-1 knockout (Cav-1−/−) and control wild-type C57 mice received one TNBS administration. Body weight and clinical scores were monitored. Colon Cav-1 and pro-inflammatory cytokine levels were quantified through ELISAs. Inflammation was evaluated through histological analysis. Results Colon Cav-1 levels were significantly decreased in TNBS-induced colitis mice when compared to normal mice and also inversely correlated with colon inflammation scores and proinflammatory cytokine levels (IL-17, IFN-γ and TNF) significantly. Furthermore, after administration of TNBS, Cav-1−/− mice showed significantly increased clinical and colon inflammatory scores and body weight loss when compared with control mice. Conclusions and Significance Cav-1 may play a protective role in the development of TNBS-induced colitis. Our findings raise an important issue in the evaluation of specific molecules in animal models that different models may exhibit opposite results because of the different mechanisms involved.
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Affiliation(s)
- Carolyn R. Weiss
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Qingdong Guan
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Yanbing Ma
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Gefei Qing
- Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Charles N. Bernstein
- Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Richard J. Warrington
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Zhikang Peng
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
- * E-mail:
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Sanders YY, Cui Z, Le Saux CJ, Horowitz JC, Rangarajan S, Kurundkar A, Antony VB, Thannickal VJ. SMAD-independent down-regulation of caveolin-1 by TGF-β: effects on proliferation and survival of myofibroblasts. PLoS One 2015; 10:e0116995. [PMID: 25658089 PMCID: PMC4319960 DOI: 10.1371/journal.pone.0116995] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 12/17/2014] [Indexed: 12/30/2022] Open
Abstract
Transforming growth factor-β (TGF-β) mediates growth-inhibitory effects on most target cells via activation of the canonical SMAD signaling pathway. This growth-inhibitory activity may be coupled with cellular differentiation. Our studies demonstrate that TGF-β1 inhibits proliferation of primary, non-transformed human lung fibroblasts in association with the induction of myofibroblast differentiation. Differentiated myofibroblasts maintain the capacity to proliferate in response to exogenous mitogenic stimuli and are resistant to serum deprivation-induced apoptosis. These proliferative and anti-apoptotic properties of myofibroblasts are related, in part, to the down-regulation of caveolin-1 (Cav-1) by TGF-β1. Cav-1 down-regulation is mediated by early activation of p38 MAPK and does not require SMAD signaling. In contrast, myofibroblast differentiation is dependent on activation of the SMAD pathway, but not on p38 MAPK. Thus, combinatorial signaling by TGF-β1 of myofibroblast differentiation and down-regulation of Cav-1 by SMAD and p38 MAPK pathways, respectively, confer proliferative and apoptosis-resistant properties to myofibroblasts. Selective targeting of this SMAD-independent, p38-MAPK/Cav-1-dependent pathway is likely to be effective in the treatment of pathological conditions characterized by TGF-β signaling and myofibroblast activation.
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Affiliation(s)
- Yan Y. Sanders
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America
| | - Zongbin Cui
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, United States of America
| | - Claude Jourdan Le Saux
- Division of Cardiology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, United States of America
| | - Jeffrey C. Horowitz
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, United States of America
| | - Sunad Rangarajan
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America
| | - Ashish Kurundkar
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America
| | - Veena B. Antony
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America
| | - Victor J. Thannickal
- Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America
- * E-mail:
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Gupta R, Toufaily C, Annabi B. Caveolin and cavin family members: dual roles in cancer. Biochimie 2014; 107 Pt B:188-202. [PMID: 25241255 DOI: 10.1016/j.biochi.2014.09.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 09/04/2014] [Indexed: 12/16/2022]
Abstract
Caveolae are specialized plasma membrane subdomains with distinct lipid and protein compositions, which play an essential role in cell physiology through regulation of trafficking and signaling functions. The structure and functions of caveolae have been shown to require the proteins caveolins. Recently, members of the cavin protein family were found to be required, in concert with caveolins, for the formation and function of caveolae. Caveolins have a paradoxical role in the development of cancer formation. They have been involved in both tumor suppression and oncogenesis, depending on tumor type and progress stage. High expression of caveolins and cavins leads to inhibition of cancer-related pathways, such as growth factor signaling pathways. However, certain cancer cells that express caveolins and cavins have been shown to be more aggressive and metastatic because of their increased potential for anchorage-independent growth. Here, we will survey the functional roles of caveolins and of different cavin family members in cancer regulation.
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Affiliation(s)
- Reshu Gupta
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada.
| | - Chirine Toufaily
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada
| | - Borhane Annabi
- Laboratoire d'Oncologie Moléculaire, Centre de Recherche BioMed, Département de Chimie, Université du Québec à Montréal, Québec H3C 3P8, Canada
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Yongsanguanchai N, Pongrakhananon V, Mutirangura A, Rojanasakul Y, Chanvorachote P. Nitric oxide induces cancer stem cell-like phenotypes in human lung cancer cells. Am J Physiol Cell Physiol 2014; 308:C89-100. [PMID: 25411331 DOI: 10.1152/ajpcell.00187.2014] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Even though tremendous advances have been made in the treatment of cancers during the past decades, the success rate among patients with cancer is still dismal, largely because of problems associated with chemo/radioresistance and relapse. Emerging evidence has indicated that cancer stem cells (CSCs) are behind the resistance and recurrence problems, but our understanding of their regulation is limited. Rapid reversible changes of CSC-like cells within tumors may result from the effect of biological mediators found in the tumor microenvironment. Here we show how nitric oxide (NO), a key cellular modulator whose level is elevated in many tumors, affects CSC-like phenotypes of human non-small cell lung carcinoma H292 and H460 cells. Exposure of NO gradually altered the cell morphology toward mesenchymal stem-like shape. NO exposure promoted CSC-like phenotype, indicated by increased expression of known CSC markers, CD133 and ALDH1A1, in the exposed cells. These effects of NO on stemness were reversible after cessation of the NO treatment for 7 days. Furthermore, such effect was reproducible using another NO donor, S-nitroso-N-acetylpenicillamine. Importantly, inhibition of NO by the known NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5 tetramethylimidazoline-1-oxy-3-oxide strongly inhibited CSC-like aggressive cellular behavior and marker expression. Last, we unveiled the underlying mechanism of NO action through the activation of caveolin-1 (Cav-1), which is upregulated by NO and is responsible for the aggressive behavior of the cells, including anoikis resistance, anchorage-independent cell growth, and increased cell migration and invasion. These findings indicate a novel role of NO in CSC regulation and its importance in aggressive cancer behaviors through Cav-1 upregulation.
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Affiliation(s)
- Nuttida Yongsanguanchai
- Pharmaceutical Technology (International) Program, Chulalongkorn University, Bangkok, Thailand
| | - Varisa Pongrakhananon
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; Cell-Based Drug and Health Products Development Research Unit, Chulalongkorn University, Bangkok, Thailand
| | - Apiwat Mutirangura
- Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yon Rojanasakul
- School of Pharmacy, West Virginia University, Morgantown, West Virginia
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; Cell-Based Drug and Health Products Development Research Unit, Chulalongkorn University, Bangkok, Thailand;
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Dendrofalconerol A sensitizes anoikis and inhibits migration in lung cancer cells. J Nat Med 2014; 69:178-90. [PMID: 25391454 DOI: 10.1007/s11418-014-0876-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 10/16/2014] [Indexed: 12/28/2022]
Abstract
Resistance to anoikis, enhanced cell motility, and growth in anchorage-independent conditions are hallmarks of highly metastatic cancer cells. The present study demonstrates the anoikis-sensitizing and anti-migration activities of dendrofalconerol A (DF-A), a pure bis(bibenzyl) isolated from the stem of Dendrobium falconeri (Orchidaceae), and its underlying mechanisms in human lung cancer H460 cells. DF-A at non-toxic concentrations significantly increased the anoikis response of the cancer cells, but caused no toxic effect on normal keratinocytes. In addition, DF-A significantly inhibited the growth of lung cancer cells in anchorage-independent conditions. Western blot analysis revealed that the anoikis-sensitizing effect of such a compound involves its ability to suppress survival signals as well as anti-apoptotic proteins, namely, activated protein kinase B (Akt) and Bcl-2. Furthermore, DF-A decreased caveolin-1 (Cav-1), a protein responsible for aggressiveness, while having no effect on Bax, Mcl-1, and activated Erk (p42/44) proteins. In the case of cell motility, DF-A exhibited strong anti-migration activity with the mechanism involving suppression of pFAK and Rho-GTP, but had no effect on Rac-GTP in lung cancer cells. Taken together, DF-A possesses anoikis-sensitizing activity along with anti-migration effects, and may be developed as a novel active compound for cancer treatment.
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Caveolin-1 regulates metastatic behaviors of anoikis resistant lung cancer cells. Mol Cell Biochem 2014; 399:291-302. [PMID: 25351339 DOI: 10.1007/s11010-014-2255-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 10/17/2014] [Indexed: 12/24/2022]
Abstract
Caveolin-1 (Cav-1), a protein component of cellular membrane, has been reported to regulate several cancer cell behaviors. However, its role on cancer metastasis in anoikis resistant cells is unknown. The present study aimed to investigate the correlation between Cav-1 level and aggressive behaviors of anoikis resistant cancer cells. Cav-1 and ShRNACav-1 stably transfected lung carcinoma cells, and anoikis resistant H_AR1 and H_AR2 cells expressing different levels of Cav-1 were subjected to anoikis, cell growth, anchorage-independent growth, extracellular matrix adhesion, cisplatin sensitivity, migration, and invasion assays. The correlations between cellular Cav-1 level and such cancer aggressive behaviors were evaluated. Results revealed that anoikis resistant lung cancer cells as well as Cav-1 overexpressing cells exhibit a significant increase in anchorage-independent growth, extracellular matrix adhesion, migration, and invasion in comparison to those of their parental H460 cells. Knock-down of Cav-1 by ShRNA transfection was able to reverse such metastatic potentials in H_AR2 cells. In addition, basal Cav-1 level of these cells was positively correlated with anoikis resistance, anchorage-independent growth, migration, and invasion behaviors of the cells, whereas such Cav-1 level showed poor correlation to cisplatin sensitivity, cell adhesion, and growth in attached condition. These findings give more information regarding role of Cav-1 in the regulation of behaviors of lung cancer cells.
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Deb M, Sengupta D, Kar S, Rath SK, Parbin S, Shilpi A, Roy S, Das G, Patra SK. Elucidation of caveolin 1 both as a tumor suppressor and metastasis promoter in light of epigenetic modulators. Tumour Biol 2014; 35:12031-47. [DOI: 10.1007/s13277-014-2502-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 08/13/2014] [Indexed: 12/12/2022] Open
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