Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional
therapies is one of the major limiting factors of
cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated
cancer cells and CSC. Here we demonstrated the potential role of proapoptotic
protein BAD in the biology of CSC in
melanoma, prostate and breast
cancers. We enriched CD44(+)/CD24(-) cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic,
ABT-737. Both pharmacological agents that inhibit survival
kinases and
growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44(+) CSC of 83%
breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in
prostate cancer, suggesting a role of BAD in
tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for
cancer therapy but also as a marker of
tumor progression.