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Open AccessArticle

Caveolin-1-Mediated Tumor Suppression Is Linked to Reduced HIF1α S-Nitrosylation and Transcriptional Activity in Hypoxia

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Cellular Communication Laboratory, Center for studies on Exercise, Metabolism and Cancer (CEMC), Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile
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Instituto Oncológico Fundación Arturo López Pérez, Santiago 7500921, Chile
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Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380000, Chile
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Laboratorio de Microbiología Celular, Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8320000, Chile
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Center for Regenerative Medicine, Faculty of Medicine, Clínica Alemana Universidad Del Desarrollo, Santiago 7710162, Chile
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Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca 3460000, Chile
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Laboratory of Immunoncology, Fundación Ciencia & Vida; Facultad de Medicina y Ciencia, Universidad San Sebastián; Santiago 7780272, Chile
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Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Karolinska Institutet, 17164 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2349; https://doi.org/10.3390/cancers12092349
Received: 5 April 2020 / Revised: 23 April 2020 / Accepted: 26 April 2020 / Published: 20 August 2020
(This article belongs to the Section Molecular Cancer Biology)
Caveolin-1 (CAV1) is a well-established nitric oxide synthase inhibitor, whose function as a tumor suppressor is favored by, but not entirely dependent on, the presence of E-cadherin. Tumors are frequently hypoxic and the activation of the hypoxia-inducible factor-1α (HIF1α) promotes tumor growth. HIF1α is regulated by several post-translational modifications, including S-nitrosylation. Here, we evaluate the mechanisms underlying tumor suppression by CAV1 in cancer cells lacking E-cadherin in hypoxia. Our main findings are that CAV1 reduced HIF activity and Vascular Endothelial Growth Factor expression in vitro and in vivo. This effect was neither due to reduced HIF1α protein stability or reduced nuclear translocation. Instead, HIF1α S-nitrosylation observed in hypoxia was diminished by the presence of CAV1, and nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) reduced HIF1α transcriptional activity in cells to the same extent as observed upon CAV1 expression. Additionally, arginase inhibition by (S)-(2-Boronoethyl)-L-cysteine (BEC) partially rescued cells from the CAV1-mediated suppression of HIF1α transcriptional activity. In vivo, CAV1-mediated tumor suppression was dependent on NOS activity. In summary, CAV1-dependent tumor suppression in the absence of E-cadherin is linked to reduced HIF1α transcriptional activity via diminished NOS-mediated HIF1α S-nitrosylation. View Full-Text
Keywords: caveolin-1; hypoxia; HIF1α; S-nitrosylation; tumor suppression; VEGF caveolin-1; hypoxia; HIF1α; S-nitrosylation; tumor suppression; VEGF
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MDPI and ACS Style

Sanhueza, C.; Bennett, J.C.; Valenzuela-Valderrama, M.; Contreras, P.; Lobos-González, L.; Campos, A.; Wehinger, S.; Lladser, Á.; Kiessling, R.; Leyton, L.; Quest, A.F.G. Caveolin-1-Mediated Tumor Suppression Is Linked to Reduced HIF1α S-Nitrosylation and Transcriptional Activity in Hypoxia. Cancers 2020, 12, 2349. https://doi.org/10.3390/cancers12092349

AMA Style

Sanhueza C, Bennett JC, Valenzuela-Valderrama M, Contreras P, Lobos-González L, Campos A, Wehinger S, Lladser Á, Kiessling R, Leyton L, Quest AFG. Caveolin-1-Mediated Tumor Suppression Is Linked to Reduced HIF1α S-Nitrosylation and Transcriptional Activity in Hypoxia. Cancers. 2020; 12(9):2349. https://doi.org/10.3390/cancers12092349

Chicago/Turabian Style

Sanhueza, Carlos; Bennett, Jimena C.; Valenzuela-Valderrama, Manuel; Contreras, Pamela; Lobos-González, Lorena; Campos, América; Wehinger, Sergio; Lladser, Álvaro; Kiessling, Rolf; Leyton, Lisette; Quest, Andrew F.G. 2020. "Caveolin-1-Mediated Tumor Suppression Is Linked to Reduced HIF1α S-Nitrosylation and Transcriptional Activity in Hypoxia" Cancers 12, no. 9: 2349. https://doi.org/10.3390/cancers12092349

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