Regulation of self-renewal in ovarian cancer stem cells by fructose via chaperone-mediated autophagy

Abstract

The chaperone-mediated autophagy (CMA) pathway is deregulated in different types of cancers; however, its role in cancer stem cells (CSCs) is unknown yet. Development of ovarian cancer, the most lethal gynecological type of cancer, involves the metastasis of CSCs to the abdominal cavity. This study aims to determine the role of CMA in ovarian CSCs. We found that the transcription factor EB (TFEB) and trehalose, a disaccharide that induces TFEB activation, enhance the expression of octamer-binding transcription factor 4 (OCT4) stem cell and lysosomal-associated membrane protein 2A (LAMP2A) CMA markers. However, trehalose did not increase the level of the LC3II macroautophagy marker in ovarian CSCs. In A2780 and SKOV3 ovarian CSCs, LAMP2A and heat shock protein 70 (HSC70) exhibited higher expression levels than in normal adherent cells. Our results showed that the silencing of the LAMP2A gene resulted in reduced sphere formation and enhanced GLUT5 expression in ovarian CSCs. Moreover, the treatment with fructose reduced sphere formation and enhanced the expression levels of LAMP2A, SOX2, and OCT4 in ovarian CSCs. The KEGG functional analysis revealed that differentially expressed genes were enriched in the ferroptosis pathway in A2780-spheroid (SP) cells after treatment with fructose. In A2780-SP and SKOV3-SP cells, the level of SLC7A11 decreased whereas FTH increased after treatment with fructose. Taken together, our results suggest that CMA is mediated in CSCs via fructose metabolism.

Keywords: Cancer stem cells; Chaperone-mediated autophagy; Fructose; LAMP2A; TFEB.