Autophagy- An emerging target for melanoma therapy

Abstract

Melanoma accounts for only 5% of all cancers but is the leading cause of skin cancer death due to its high metastatic potential. Patients with metastatic melanoma have a 10-year survival rate of less than 10%. While the clinical landscape for melanoma is evolving rapidly, lack of response to therapies, as well as resistance to therapy remain critical obstacles for treatment of this disease. In recent years, a myriad of therapy resistance mechanisms have been unravelled, one of which is autophagy, the focus of this review. In advanced stages of malignancy, melanoma cells hijack the autophagy machinery in order to alleviate drug-induced and metabolic stress in the tumor microenvironment, thereby promoting resistance to multiple therapies, tumor cell survival, and progression. Autophagy is an essential cellular process that maintains cellular homeostasis through the recycling of intracellular constituents. Early studies on the role of autophagy in cancer generated controversy as to whether autophagy was pro- or anti-tumorigenic. Currently, there is a consensus that autophagy is tumor-suppressive in the early stages of cancer and tumor-promoting in established tumors. This review aims to highlight current understandings on the role of autophagy in melanoma malignancy, and specifically therapy resistance; as well as to evaluate recent strategies for therapeutic autophagy modulation.

Keywords: autophagy; melanoma; tumor.

Figure 1.. Process of autophagy.

Initiation of the autophagy process is mediated by the ULK1 complex in response to various cellular signals. Formation of the phagophore also requires class III phosphoinositide 3-kinase (PI3K) complex, which is composed of VPS34 (vacuolar protein sorting 34) PI3K, ATG14L, VPS15, and beclin 1. The ATG5-ATG12-ATG16 complex and LC3II promote the elongation of the phagophore and are required for the formation of the autophagosome. p62 bound to ubiquitinated proteins targeted for degradation binds to lipidated microtubule-associated protein light chain 3 (LC3II) during the formation of the autophagosome as intracellular materials are engulfed into the forming autophagosome. Subsequently, the autophagosome fuses with a lysosome, which delivers hydrolytic enzymes for the degradation of the engulfed intracellular material.