Abstract
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.
Highlights
Caveolin-1 (CAV1), a member of the caveolin family of proteins [1,2,3], is a scaffolding protein with a controversial role in cancer, given that it has been ascribed roles both as a tumor suppressor and a promoter of metastasis [4,5]
CAV1 knockdown in MDA-MB-231 cells increased vascular endothelial growth factor A (VEGF-A) and glucose transporter 1 (GLUT-1), but not lactate dehydrogenase (LDH)-A expression in hypoxia (Figure 2D). These results strongly indicate that CAV1 presence in different cancer cells reduces hypoxia-inducible factor-1α (HIF1α) activity and concomitantly target gene expression in hypoxia
We found that the levels of HIF1α S-nitrosylation were reduced (~35%) in cells expressing CAV1 (C14) compared to Mock (M1) cells (Figure 4C)
Summary
Caveolin-1 (CAV1), a member of the caveolin family of proteins [1,2,3], is a scaffolding protein with a controversial role in cancer, given that it has been ascribed roles both as a tumor suppressor and a promoter of metastasis [4,5] Work from this laboratory has shown that CAV1 sequesters β-catenin to the plasma membrane in a multi-protein complex with E-cadherin, thereby precluding the β-catenin/T-cell factor-Lymphoid enhancer factor (Tcf-Lef)-dependent transcription of genes, including survivin and cyclooxygenase-2 (COX-2), both of which are important for tumor cell survival, and in doing so, reducing cancer cell viability [6,7,8]. In this study, we evaluate whether E-cadherin-independent tumor suppression by CAV1 might be linked to the ability of CAV1 to reduce S-nitrosylation and, HIF1α activation in hypoxia
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