The role of chaperone-mediated autophagy in drug resistance

Abstract

In the search for alternatives to overcome the challenge imposed by drug resistance development in cancer treatment, the modulation of autophagy has emerged as a promising alternative that has achieved good results in clinical trials. Nevertheless, most of these studies have overlooked a novel and selective type of autophagy: chaperone-mediated autophagy (CMA). Following its discovery, research into CMA's contribution to tumor progression has accelerated rapidly. Therefore, we now understand that stress conditions are the primary signal responsible for modulating CMA in cancer cells. In turn, the degradation of proteins by CMA can offer important advantages for tumorigenesis, since tumor suppressor proteins are CMA targets. Such mutual interaction between the tumor microenvironment and CMA also plays a crucial part in establishing therapy resistance, making this discussion the focus of the present review. Thus, we highlight how suppression of LAMP2A can enhance the sensitivity of cancer cells to several drugs, just as downregulation of CMA activity can lead to resistance in certain cases. Given this panorama, it is important to identify selective modulators of CMA to enhance the therapeutic response.

Figure 1 -. CMA mechanism. The CMA pathway is initiated by recognition of the target protein in the cytosol by binding of the Hsc70 chaperone to the KFERQ motif present in the substrate (1). Subsequently, the substrate is directed to the surface of the lysosome membrane and encounters LAMP2A (2), which forms a multimeric complex (3), allowing protein translocation into the lysosomal lumen (4). Upon complete protein degradation (5), LAMP2A returns to its monomeric state (6) to initiate new processes and translocations. Created with BioRender.

Figure 2 -. CMA is influenced by and regulates the tumor microenvironment. The stress condition of the tumor microenvironment is the primary signal for the activation of CMA. Specifically, nutrient restriction, hypoxia and NRF2 pathway are well-documented CMA activators. On the other hand, CMA degrades important proteins such as KEAP-1, N-Cor, p53, RND3 and HSD17B4, which supports the tumor microenvironment, resulting in the progression of cancer by increasing NRF2, promoting cell survival and growth, sustaining the Warburg effect, regulating the cell cycle, and promoting cell invasion and migration. Created with BioRender.