TFEB mediated autophagy upregulate to inhibit apoptosis in endometriosis
Autophagy and apoptosis are the main factors determining cell fate. Apoptosis is a kind of cell death characterized by cell atrophy, chromatin condensation and other morphological changes. Autophagy, which means ”self-feeding” is an important degradation pathway to eliminate protein aggregation and damaged organelles in cells.(74) More and more evidence show that apoptosis and autophagy have antagonistic effects. Autophagy helps human cancer cells survive through apoptotic resistance, and inhibition of autophagy leads to caspase-dependent apoptotic cell death.(75) In tumor microenvironment, inhibition of autophagy disrupts cell metabolism, causes genomic instability, interferes with differentiation, and destroys anti-cancer immune surveillance. During tumor development, cancer cells are exposed to different types of stress, including nutritional deficiency, metabolic stress and hypoxia, especially in the central region of the tumor. Autophagy can be reinstated which can increase the resistance of cancer cells to chemotherapy or radiotherapy.(76) The cytoprotective effect of autophagy can maintain the survival ability of tumor cells and prevent the apoptosis of cancer cells.(77) In nucleus pulposus cells, TFEB overexpression enhanced autophagy flux and lysosome function, which further protected nucleus pulposus cells from apoptosis and senescence induced by TBHP (ROS donor induced oxidative stress).(78) The same mechanism may exist in endometriosis. In early stage of endometriosis, inhibition of autophagy disrupts cell metabolism, interferes with differentiation, and evades immune surveillance. As the disease progresses, excessive ROS activates TFEB in different ways, and overexpression of TFEB promotes the expression of autophagy-related proteins, increases the autophagy flux and lysosome synthesis,thus maintaining cell growth and inhibiting apoptosis, leading to the worsening of endometriosis. It was reported that the expression of Bcl-2 was increased in ectopic endometriosis in ovarian endometriosis patients. Bcl-2 is an important anti-apoptotic regulator, and its increase is associated with impaired spontaneous apoptosis, indicating that apoptosis is decreased in endometrioma.(79)