Adipocyte microenvironment promotes Bclxl expression and confers chemoresistance in ovarian cancer cells

Resistance to mitochondria-initiated apoptosis is a hallmark of chemoresistant cancer stem cells including CD44+/MyD88+ epithelial ovarian cancer (EOC) stem cells. This is controlled by members of the Bcl(2) family of proteins, which function as rheostats of mitochondrial stability. We observed a differential expression profile of Bcl(2) family members comparing the chemoresistant EOC stem cells and the chemosensitive CD44-/MyD88- EOC cells. Chemoresistant EOC stem cells surprisingly express higher levels of the pro-apoptotic members Bak and Bax compared to the chemosensitive EOC cells. In addition, whereas chemosensitive EOC cells preferentially express Bcl(2), chemoresistant EOC stem cells preferentially express Bcl(xl). In the EOC stem cells, 40% knock-down of Bcl(xl) expression was sufficient to induce the full activation of caspases and this can be reversed by concurrent knock-down of Puma. More importantly, we demonstrate that Bcl(xl) expression levels in EOC cells is dynamic and can be regulated by microenvironments that are enriched with the pro-inflammatory cytokine IL-6 such as the cancer stem cell and adipocyte niches. Adipocyte-induced upregulation of Bcl(xl) correlated with acquisition of chemoresistance and thus demonstrates how a specific microenvironment can regulate the expression of apoptotic proteins and confer chemoresistance.