Modulating autophagy for the therapeutic benefit of cutaneous melanoma

Abstract

Cutaneous metastatic melanoma remains largely untreatable, likely due to resistance to apoptosis and/or the activation of pro-survival signalling. Incidence continues to increase highlighting the urgent need for more effective treatment strategies. Many chemotherapeutic drugs induce autophagy, the principle lysosomalmediated mechanism for the degradation/recycling of cellular products, as a compensatory mechanism to counteract apoptotic signals leading to the development of autophagy inhibition as a treatment for metastatic cancer. However, how to modulate autophagy for therapeutic benefit remains debatable since recent approaches demonstrate autophagy induction may also result in cell death in some tumour types. In line with the increasing evidence linking autophagy and apoptosis, including the discovery of interactions between anti-apoptotic Bcl-2 proteins and the autophagy regulatory protein Beclin-1, the principle aim of this study was thus to determine how autophagy modulation in metastatic melanoma may be harnessed for clinical benefit. To this aim drugs which activate pro-survival (bortezomib) or cytotoxic (Tetrahydrocannabinol, THC) autophagy were combined with a number of approaches to dissect the role of autophagy during cell death in response to these agents. Results demonstrated that while the anti-apoptotic protein Mcl-1 was able to limit autophagy, its over-riding function was the direct regulation of apoptosis. Furthermore, results confirmed autophagy was required for THC-induced death of melanoma cells, but that neither Beclin-1 nor Ambra 1 were required for autophagy, suggesting non-canonical autophagy activation in response to THC. Finally, THC was shown to promote lysosome membrane permeabilization (LMP) which was required for cell death. In conclusion, these data suggest THC-induced apoptosis of melanoma cells requires induction of autophagy which, coupled with the activation of LMP that is also dependent on autophagic signalling, suggests a novel link between the processes of autophagy and apoptosis, ultimately translating into novel strategies through which to harness autophagy for the therapeutic benefit of melanoma.