Chaperone-Mediated Autophagy Is Required for Tumor Growth

Abstract

The cellular process of autophagy (literally “self-eating”) is important for maintaining the homeostasis and bioenergetics of mammalian cells. Two of the best-studied mechanisms of autophagy are macroautophagy and chaperone-mediated autophagy (CMA). Changes in macroautophagy activity have been described in cancer cells and in solid tumors, and inhibition of macroautophagy promotes tumorigenesis. Because normal cells respond to inhibition of macroautophagy by up-regulation of the CMA pathway, we aimed to characterize the CMA status in different cancer cells and to determine the contribution of changes in CMA to tumorigenesis. Here, we show consistent up-regulation of CMA in different types of cancer cells regardless of the status of macroautophagy. We also demonstrate an increase in CMA components in human cancers of different types and origins. CMA is required for cancer cell proliferation in vitro because it contributes to the maintenance of the metabolic alterations characteristic of malignant cells. Using human lung cancer xenografts in mice, we confirmed the CMA dependence of cancer cells in vivo. Inhibition of CMA delays xenograft tumor growth, reduces the number of cancer metastases, and induces regression of existing human lung cancer xenografts in mice. The fact that similar manipulations of CMA also reduce tumor growth of two different melanoma cell lines suggests that targeting this autophagic pathway may have broad antitumorigenic potential.

Ebb-and-Flow of Macroautophagy and Chaperone-Mediated Autophagy in Raji Cells Induced by Starvation and Arsenic Trioxide

“…In summary, the results of this research confirm a previously little-known cross-talk between macroautophagy and CMA in lymphoma Raji cells facing different stressors, and these findings must be helpful to understanding the characteristics, compensatory mechanisms and answer mode of different autophagic pathways in cancer cells, which may be very important and promising to the development of interventions targeting regulate one form of autophagy for potential targeting therapeutic purposes in human diseases, such as cancer or neurodegenerative disorders (Kon et al, 2011;Saha, 2012;Xilouri et al, 2013). Up-regulation of one autophagic pathways after the failure of another particular form of autophagy can be the basis for future therapeutic interventions to preserve normal cellular function in these pathologies.…”

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A

“…It is thus possible that different transcription factors co-exist to assure proteostasis under several circumstances and in distinct cell types. In fact, levels of basal CMA activity and the amplitude of the induction varies among different cell types [12,16,36,37]. Importantly, this novel NFE2L2-LAMP2A axis is conserved in different cell types.…”

Chaperone-mediated autophagy: roles in disease and aging

“…For example, degradation of inhibitors of transcription factors by CMA during starvation has already been demonstrated for specific transcription programs [34]. Likewise, degradation of regulatory metabolic enzymes by CMA has been shown to contribute to the metabolic changes that allow, for example, for cancer cells to adapt to low nutrient conditions [17,35]. The other important function that CMA fulfills in cells is quality control, directly linked to the ability of this pathway to selectively remove single proteins from the cytosol ( Figure 1B).…”