Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

Abstract

Melanoma cells depend on sustained proteasomal function for survival. However, bortezomib, the first proteasome inhibitor in clinical use, is not sufficient to improve the poor prognosis of metastatic melanoma patients. Since the proteasome is also expressed in all normal cell compartments, it is unclear how to enhance the efficacy of bortezomib without exacerbating secondary toxicities. Here, we present pharmacological and genetic analyses of mechanisms of resistance to proteasome inhibition. We focused on Bcl-2, Bcl-x L and Mcl-1 as main antiapoptotic factors associated with melanoma progression. Despite an efficient blockage of the proteasome, bortezomib could not counteract the intrinsically high levels of Bcl-2 and Bcl-x L in melanoma cells. Moreover, Mcl-1 was only downregulated at late time points after treatment. Based on these results, a combination treatment including (À)-gossypol, an inhibitor of Mcl-1/Bcl-2/Bcl-x L , was designed and proven effective in vivo. Using a specific RNA interference approach, the survival of bortezomib-treated melanoma cells was found to rely primarily on Mcl-1, and to a lesser extent on Bcl-x L (but not on Bcl-2). Importantly, neither Mcl-1 nor Bcl-x L inactivation affected the viability of normal melanocytes. This hierarchical requirement of Bcl-2 family members for the maintenance of normal and malignant cells offers a therapeutic window to overcome melanoma chemoresistance in a tumor cell-selective manner.

Down-Regulation of Mcl-1 by Small Interfering RNA Sensitizes Resistant Melanoma Cells to Fas-Mediated Apoptosis

“…Our studies might suggest a functional hierarchy of the antiapoptotic Bcl-2 proteins in melanoma cells resistant to Fas-induced apoptosis; Mcl-1 is required, as well as, to a significantly lesser extent, Bcl-2 and perhaps Bcl-xL. This is in line with recent evidence about the function of Bcl-2 -related proteins in resistance of melanoma cells to bortezomib-induced death (48). Beside, the implication of additional antiapoptotic proteins in the resistance of melanoma cells to Fas-mediated apoptosis is not excluded.…”

MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma

“…S12, only WT p53 was shown to significantly enhance miR149* promoter activity, suggesting that p53 is the bona fide regulator of miR149* expression. Up-regulation of Mcl-1 is known to be induced by ER stress and is one of the major prosurvival mechanisms of melanoma cells (5,40). Thus, an unexpected function of p53 in promoting Mcl-1 expression via miR-149* and GSK3α provides an advantage for melanoma cell survival and conceivably resistance to treatment.…”

Salinomycin in cancer: A new mission for an old agent

“…This might be one reason why salinomycin can overcome multiple mechanisms of drug and apoptosis resistance in human cancer cells. Many cancer cells harbor or acquire multiple mechanisms of apoptosis resistance mediated by the loss of p53 and overexpression of Bcl-2, P-glycoprotein or 26S proteasomes with enhanced proteolytic activity (42)(43)(44). Salinomycin, however, appears to be capable of overcoming these mechanisms of drug and apoptosis resistance, suggesting a possible future use of salinomycin in the treatment of drug-resistant and aggressive cancers.…”