Chaperone-mediated autophagy regulates proliferation by targeting RND3 in gastric cancer

Abstract

LAMP2A is the key protein of chaperone-mediated autophagy (CMA), downregulation of LAMP2A leads to CMA blockade. CMA activation has been implicated in cancer growth, but the exact mechanisms are unclear. Elevated expression of LAMP2A was found in 8 kinds of tumors (n=747), suggesting that LAMP2A may have an important role in cancer progression. Unsurprisingly, LAMP2A knockdown in gastric cancer (GC) cells hindered proliferation, accompanied with altered expression of cell cycle-related proteins and accumulation of RND3/RhoE. Interactomic and KEGG analysis revealed that RND3 was a putative CMA substrate. Further study demonstrated that RND3 silencing could partly rescue the proliferation arrest induced by LAMP2A knockdown; RND3 was increased upon lysosome inhibition via both chemicals and LAMP2A-shRNA; Furthermore, RND3 could interact with CMA components HSPA8 and LAMP2A, and be engulfed by isolated lysosomes. Thus, constant degradation of RND3 by CMA is required to sustain rapid proliferation of GC cells. At last, the clinical significance of LAMP2A was explored in 593 gastric noncancerous lesions and 173 GC tissues, the results revealed that LAMP2A is a promising biomarker for GC early warning and prognosis of female GC patients.

Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation

“…19,20 However, like other autophagic pathways such as macroautophagy, 6,36,37 the contribution of CMA to cancer cell proliferation and tumor growth seems to be context dependent. Thus, studies in other types of cancer cells have proposed a negative effect of CMA on cancer cell biology through degradation of oncogenic proteins such as TP53 protein 38,39 or HK2 (hexokinase 2).…”

“…7 Thus, CMA inhibition in malignant cells lowers cellular proliferation and reduces tumorigenic and metastatic capacity. 7,19 Later reports have confirmed this dependence on CMA for cancer cell growth and attribute it to a diversity of mechanisms including: protection against oxidative damage, 19 removal of negative regulators of cell proliferation 20 and antioncogenes 21 or maintenance of the metabolic switch favorable for cancer cell growth. 22,23 However, the role of CMA on early stages of tumor development such as transformation of normal cells into cancerous cells has not been elucidated.…”

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

“…The cellular pathways and physiological importance of CMA in cancer still needs to be delineated 91 . It has been reported that high basal CMA activity is a common feature among different types of human tumors 92 . In contrast to normal cells, this upregulation of CMA occurs independent of the macroautophagy status of cancerous cells.…”

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

“…CMA may also improve resistance to various stress inducing stimuli including chemotherapy [56], ER stress [57] and hypoxia [58,59]. Lastly, CMA may contribute to tumor cell proliferation and metastatic potential [52,[60][61][62]. While constitutively active CMA was frequently found in cancer cells [52], a study reported that the lack of Lamp2A expression in mice increased the risk of malignant transformation and liver tumorigenesis [63].…”