Studies
of the
Cell
Cellular Communication
Group Leader : ANDREW F.G. QUEST
Project Description
Research in this laboratory focuses on addressing two major questions: First, understanding the role of a membrane-associated protein called caveolin-1 in cancer is major objective; second, understanding mechanisms that lead to alternative forms of cell death like necrosis, particularly in cancer cells, is of interest.
Caveolin-1 related work. Cancer is a leading cause of morbidity and mortality in humans. Results from the literature have implicated the protein caveolin-1 as a tumor suppressor protein in a variety of cellular settings (summarized in Quest et al., 2004).
Data from this laboratory demonstrated that caveolin-1 expression is down-regulated in human colon cancer and re-expression of the protein in human colon adeonocarcinoma cell lines is sufficient to reduce tumor formation in nude mice (Bender et al., 2000; Bender et al., 2002). Thus, caveolin-1 functions as a tumor suppressor in this particular cellular background and efforts in the laboratory have focused on identifying mechanisms that explain this ability. Specifically, we have identified the inducible isoform of nitric oxide synthase (iNOS), implicated as an epigenetic factor linked to cancer progression, as a downstream target. Caveolin-1 was shown to reduce iNOS levels via a novel, unanticipated post-transcriptional mechanism that involves recruitment of the protein to detergent insoluble membrane microdomains via a putative WW-domain and subsequent proteasome-mediated degradation of the protein (Felley-Bosco et al., 2000; 2002).
More recently, a screen for differences between cancer cells expressing or not caveolin-1 identified the inhibitor of apoptosis protein (IAP) survivin as a downstream transcriptional target whose expression is controlled via the β-catenin/Tcf-Lef pathway. This protein is of particular interest in cancer biology given that its expression is augmented in essentially all human tumors and is associated with enhanced viability and malignancy of tumor cells. Consistent with this notion, work from this lab has shown that inhibitors of the kinase CK2 promote tumor cell death and do so by precluding the ability of this kinase to promote β-catenin/Tcf-Lef-dependent transcription of survivin (Tapia et al., 2006). Likewise, caveolin-1 recruits β-catenin to the plasma membrane, thereby reducing the cytosolic pool available for transcription of survivin and, in doing so, reduces cell viability (Torres et al., 2006).
Evidence available in the literature indicates that caveolin-1 function is cell context dependent and that it may both act as a tumor suppressor or, to the contrary, promote for instance metastasis (discussed in Quest et al., 2008). Mechanistically speaking, this dramatic switch in function remained an enigma until recently when studies from this laboratory showed that caveolin-1 is only able to suppress survivin expression in the aforementioned manner in cancer cells when E-cadherin is present (Torres et al., 2007). Thus, caveolin-1 is a conditional tumor suppressor protein whose function in part depends on the presence of E-cadherin.
Future studies seek to achieve the following objectives: 1) To identify other targets like survivin relevant to cancer biology that are regulated in a similar fashion by caveolin-1; 2) to analyze how E-cadherin modulates caveolin-1 function in vivo; and 3) to develop in vivo models that will allow the identification of molecular traits in caveolin-1 associated with its role either as a tumor suppressor or promotor of metastasis.
Cell death related work. Finally, the general interest of this laboratory in lipids and lipid second messengers has lead to a studies that linked delayed elevation of ceramide downstream of the Fas receptor to caspase-dependent necrotic cell death in lymphocytes (Hetz et al., 2002; Hetz et al., 2005). This unconventional cell death mode relies on the production of reactive oxygen species following ceramide-induced damage to the mitochondria and subsequent GSH and ATP depletion (Villena et al., 2008). Our interest in obtaining a better understanding of such unorthodox modes of cell death resides in their potential to facilitate development of drugs that may be employed to induce selective cell death in tumor cells (discussed in Diaz et al., 2005; Henriquez et al., 2008).
