Caveolin-1-mediated changes in the metabolism of cancer cells
Metabolism in tumor cells: The cancer hallmarks defined by Hanahan and Weinberg (2000), Cell 100, 57-70; Hanahan and Weinberg (2011), Cell 144, 646-674. Identified in general terms the nature of the changes that are required to transform normal cells into tumor cells. Amongst these, metabolic changes, including the Warburg effect are now recognized as crucial to the development of the transformed phenotype. Thus, processes that facilitate cell survival under conditions of metabolic stress appear to be important in the development of tumors. In this laboratory, we focus specifically on how the scaffolding protein Caveolin-1 (CAV1) participates in the pathogenesis of cancer by modulating adaptative stress responses during tumor formation.
Caveolin-1 in signalling: The Quest laboratory has a long-standing interest in understanding the role of the scaffolding protein CAV1 in cancer and particularly how in the context of a tumor cell the function of the protein may change from being a tumor suppressor to promoting metastasis. In this respect, studies from our lab have linked the tumor suppressor function of CAV1 to inhibition of -catenin/Tcf-Lef dependent transcription of cancer genes, like survivin and cyclooxygenase-2 (COX2) (Torres, Tapia et al. 2006; Rodriguez, Tapia et al. 2009). However, the ability to sequester b-catenin to the plasma membrane and preclude transcriptional activity via -catenin/TCF-Lef depends on the presence of E-cadherin (Torres, Tapia et al. 2007; Rodriguez, Tapia et al. 2009).
Consistent with these data, expression of CAV1 together with E-cadherin in the murine melanoma cell line B16F10 reduces cell proliferation, enhances cell death and completely abolishes tumor formation upon subcutaneous injection into syngenic C57BL6 mice (Lobos et al., 2013; 2014; Quest et al., 2013). None-the-less, CAV1 was also found to act as a tumor suppressor, albeit less efficiently, in the absence of E-cadherin. Of note, in B16F10 cells expressing caveolin-1 in the absence of E-cadherin, most caveolin-1 is intracellular. Moreover, in HT29(US) human colon cancer cells, metastatic derivatives of HT29 cells available at ATCC, which essentially lack E-cadherin, tumor suppression by caveolin-1 is also observed. Here, we posit that such intracellular CAV1 regulates cellular stress responses and metabolic events that are important for function as a tumor suppressor.
Adaptative responses in cancer cells: For tumors to develop, cancer cells need to adapt to the hostile conditions in their microenvironment. Accelerated proliferation leads to hypoxia within the tumor interior due to insufficient vascularization, as well as metabolic changes associated with the lack of oxygen (Warburg effect) and acidosis. Cells respond to hypoxic stress by inducing transcriptional events essential to adaptation (metabolic or otherwise) dependent on the hypoxia induced factor-1 (HIF1).
These conditions also lead to problems associated with correct folding of proteins in the endoplasmic reticulum (ER) referred to as the Unfolded Protein Response (UPR). Autophagy is another crucial biological process for the survival of cancer cells under conditions of nutrient deprivation that participates in the maintenance of cellular homeostasis by controlling the quality of proteins and cytoplasmic organelles. All the aforementioned responses are crucial to cancer cell survival in the nascent tumor. This group seeks to determine how the function of CAV1 as a tumor suppressor in the absence of E-cadherin is linked to its ability to prevent such adaptative responses in cancer cells.