Abstract 459: Caveolin-1 mediated signaling and proliferation is regulated through the oxygen sensing pathway

Caveolin-1 (Cav-1) is a multifunctional scaffolding protein with multiple binding partners that is associated with cell surface caveolae and the regulation of lipid raft domains. Cav-1 regulates multiple cancer-associated processes including cellular transformation, tumour growth, cell death and survival, and multidrug resistance. A high expression of Cav-1 is found in various cancer , including clear cell renal cell carcinoma (CCRCC), correlating with large, high grade tumors and poor prognosis. However, the role of Cav-1 in the oncogenesis of CCRCC remains unclear, and its role as either an oncogene or tumour suppressor is still under debate. Here, we investigated the mechanism of Cav-1 in controlling cell proliferation using in vitro and in vivo assays. We report that Cav-1 is highly expressed in tumour compared to normal tissue in patients with CCRCC, thus Cav-1 likely functions as an oncogene. Upon knock-down of Cav-1, tumour cells (786-VHL-/-) showed a decrease in proliferation. We showed that Cav-1 is associating with EGFR, a receptor tyrosine kinase, to activate the Ras-RAF-MEK-ERK kinase pathway and induce cell proliferation. We found that Cav-1 binds to EGFR in immunoprecipitation. The Ras pathway is upregulated in cells overexpressing Cav-1 after EGF stimulation. Upon knockdown of Cav-1, the level of p-ERK, p-MEK, and p-c-Raf decreased, as well as the rate of cell proliferation. Upstream of the Ras pathway, we report that Cav-1 appears to be under the control of hypoxia-inducible factor (HIF). Under hypoxia, VHL (the principal negative regulator of HIF) is downregulated, thus leading to upregulation of HIF. We showed that under hypoxia, Cav-1 increased in 786-VHL, Hela and A431 cell lines. Similarly, cells with VHL loss (786-VHL-/-), thus high HIF level, had high levels of Cav-1. We are currently examining the role of Cav-1 in tumour growth by injecting SCID mice with either 786-VHL-/-, or Cav-1 knock-down 786-VHL-/- tumour cells. Since Cav-1 level seems to be under the control of HIF in renal, cervical and squamous carcinoma cell lines, it suggests that the oxygen sensing pathway plays a general role in controlling cell proliferation through upregulating Cav-1. Cav-1 should be considered as a target for drug design as the knock down of Cav-1 decreased cell proliferation and could potentially decrease tumour growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 459.