Melanoma LAMP-2C Modulates Tumor Growth and Autophagy

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.

Loss of chaperone-mediated autophagy is associated with low vertebral cancellous bone mass

“…Lamp2c is expressed at the highest level in the brain and this high endogenous Lamp2c level has been proposed to mediate lysosomal degradation of RNA in this tissue 36 . Although endogenously expressed at low levels, inflammatory conditions increase Lamp2c levels in B cells 37 and melanoma cells 39 . Strong overexpression of Lamp2c in melanoma 39 and B cells 37 has been reported to inhibit macroautophagy and CMA in these cell types, suggesting potential roles of LAMP2C in these cell types under inflammatory conditions.…”

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

“…(3) the transcription factor nuclear factor, erythroid derived 2, such as 2 (NFE2L2/NFR2) regulates expression of Lamp2a, being the NFE2L2 deficiency associated with reduced LAMP2A levels [159]; (4) retinoic acid receptor alpha (RARα) has been found to negatively regulate LAMP2A expression, and the RARα activator all-trans retinoic acid (ATRA) acts as a potent LAMP2A inhibitor [160]; (5) endoplasmic reticulum (ER) stress mediates p38MAPK activation which in turns phosphorylates LAMP2A and promotes CMA, a mechanism termed "ERICA" (ER stress-induced chaperone-mediated autophagy) [161]; (6) Phosphopeptide P140, a fragment of the spliceosomal SNRNP70/U1-70K protein, has been reported to alter the composition of HSPA8/HSC70 complexes and down-regulates LAMP2A expression, thereby reducing CMA [162]; and (7) Unlike LAMP2A, the only LAMP2 isoform that participates in CMA, LAMP2C negatively regulates melanoma growth and survival [163].…”

Germline FOXJ2 overexpression causes male infertility via aberrant autophagy activation by LAMP2A upregulation

“…We then asked the question: what is the effect of overexpression of Foxj2 on the autophagy process at the initiation of meiosis in spermatogenesis? According to the literature, there are three different isoforms of LAMP2 arising from alternative mRNA splicing, known as LAMP2A, LAMP2B, and LAMP2C, which function in different types of autophagy, namely CMA, macroautophagy, and RNautophagy/DNautophagy, respectively [ 23 , 24 ]. We then tested the expression of the isoforms of Lamp2 in the testis and found that the mRNA expression level of Lamp2a in the testes of Stra8-cre; Foxj2 tg/tg mice was significantly higher than that of the WT, while there were no significant differences in the mRNA expression levels of Lamp2b or Lamp2c between the Stra8-cre; Foxj2 tg/tg and WT mice (Fig.…”