Abstract
Autophagy plays critical but diverse roles in cellular quality control and homeostasis potentially checking tumor development by removing mutated or damaged macromolecules, while conversely fostering tumor survival by supplying essential nutrients during cancer progression. This report documents a novel inhibitory role for a lysosome-associated membrane protein, LAMP-2C in modulating autophagy and melanoma cell growth in vitro and in vivo. Solid tumors such as melanomas encounter a variety of stresses in vivo including inflammatory cytokines produced by infiltrating lymphocytes directed at limiting tumor growth and spread. Here, we report that in response to the anti-tumor, pro-inflammatory cytokine interferon-gamma, melanoma cell expression of LAMP2C mRNA significantly increased. These results prompted an investigation of whether increased melanoma cell expression of LAMP-2C might represent a mechanism to control or limit human melanoma growth and survival. In this study, enhanced expression of human LAMP-2C in melanoma cells perturbed macroautophagy and chaperone-mediated autophagy in several human melanoma lines. In vitro analysis showed increasing LAMP-2C expression in a melanoma cell line, triggered reduced cellular LAMP-2A and LAMP-2B protein expression. Melanoma cells with enhanced LAMP-2C expression displayed increased cell cycle arrest, increased expression of the cell cycle regulators Chk1 and p21, and greater apoptosis and necrosis in several cell lines tested. The increased abundance of Chk1 protein in melanoma cells with increased LAMP-2C expression was not due to higher CHEK1 mRNA levels, but rather an increase in Chk1 protein abundance including Chk1 molecules phosphorylated at Ser345. Human melanoma cell xenografts with increased LAMP-2C expression, displayed reduced growth in immune compromised murine hosts. Melanomas with high LAMP-2C expression showed increased necrosis and reduced cell density upon histological analysis. These results reveal a novel role for LAMP-2C in negatively regulating melanoma growth and survival.
Highlights
Basal levels of autophagy are critical to cellular homeostasis by eliminating malfunctioning organelles and long-lived proteins (Levine and Kroemer, 2008)
A twofold to threefold induction of LAMP2C mRNA was observed upon melanoma cells exposure to IFN-γ with very modest changes in the more abundant LAMP2A and no induction of LAMP2B (Figure 1A)
Immunohistochemical analysis of early and late stage melanomas revealed that late stage tumors associated with poor prognosis, expressed reduced levels of p62, a protein whose turnover is linked to enhanced MA (Ellis et al, 2014)
Summary
Basal levels of autophagy are critical to cellular homeostasis by eliminating malfunctioning organelles and long-lived proteins (Levine and Kroemer, 2008). While basal autophagy may function as a tumor suppressor, increased or induced autophagy may contribute to tumor survival during cancer progression (Morselli et al, 2009; Choi, 2012). Two forms of autophagy, MA and CMA are detectible in human cells and upregulated in many tumors (Morselli et al, 2009; Kon et al, 2011; Choi, 2012). During nutrient or growth factor deprivation, MA and CMA are upregulated to promote cell survival by recycling building blocks, modulating bioenergetics, and shifting metabolism. With tumor progression and exposure to metabolic stresses, MA is induced to recycle nutrients, favor tumor survival and resistance to anti-cancer therapies (Morselli et al, 2009; Choi, 2012). Hyper-expression of LAMP-2A is observed in tumors, while disrupting LAMP-2A expression slows tumors growth and metastasis (Kon et al, 2011; Zhou et al, 2016)
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