Crosstalk between autophagy and CSCs: molecular mechanisms and translational implications

Abstract

Cancer stem cells(CSCs) play a key role in regulating tumorigenesis, progression, as well as recurrence, and possess typical metabolic characteristics. Autophagy is a catabolic process that can aid cells to survive under stressful conditions such as nutrient deficiency and hypoxia. Although the role of autophagy in cancer cells has been extensively studied, CSCs possess unique stemness, and their potential relationship with autophagy has not been fully analyzed. This study summarizes the possible role of autophagy in the renewal, proliferation, differentiation, survival, metastasis, invasion, and treatment resistance of CSCs. It has been found that autophagy can contribute to the maintenance of CSC stemness, facilitate the tumor cells adapt to changes in the microenvironment, and promote tumor survival, whereas in some other cases autophagy acts as an important process involved in the deprivation of CSC stemness thus leading to tumor death. Mitophagy, which has emerged as another popular research area in recent years, has a great scope when explored together with stem cells. In this study, we have aimed to elaborate on the mechanism of action of autophagy in regulating the functions of CSCs to provide deeper insights for future cancer treatment.

Fig. 1. Autophagy promotes cancer stem cell renewal, proliferation and differentiation.

A: The morphological process of autophagy mainly includes the formation of phagocytic vesicles, the formation of autophagosomes, and the formation of autolysosomes. B: Lupeol reduces CSCs differentiation through the PI3K/AKT/mTOR pathway [45]. AMBRA1 regulates the growth and proliferation of CSCs through the c-MYC/AMBRA1/STAT3 axis [41]. CCND1 can inhibit CSCs differentiation by inhibiting BCL1 [51]. Inhibition of ULK1 enhances TKI sensitivity and induces CSCs differentiation [50]. C: ATG5 and NRF2 form a positive feedback regulation loop, and CSCs update is increased by adjusting ROS [31]. HDAC6 mediated CSC growth inhibition is further enhanced under the induction of ATG12 [49]. HULC upregulates CyclinD1 through the LC3-miR675-PKM2 pathway to accelerate the growth of CSCs [39]. MiR-200b can inhibit RAB37 activity and LC3, reducing cell viability [36]. MiR24-2 also promotes the malignant progression of CSCs by enhancing the epigenetics of tyrosine kinase through LC3y [38]. D: AMPK-FIS1 pathway can affect the self-renewal of CSCs [26, 119]. When mitophagy is inhibited, p53 co-localizes with mitochondria. PINK1 binds to the NANOG promote to accelerate the growth of CSCs [135]. BNIP3L dependent mitophagy promotes enhanced CSCs activity induced by HBx [123]. PDGF-METTL3-OPTN can inhibit mitophagy to maintain their stemness [124]. MicroRNA-137 has also been demonstrated to maintain homeostasis by inhibiting mitophagy [121].

Fig. 2. The role of autophagy in cancer stem cells.

In summary, autophagy plays approximately five roles in cancer stem cells. Autophagy can affect NOTCH, NANOG, PI3K-AKT, SOX2 through LC3, BCL-1, Ambra1, ATG5, mTOR- β- Actin signaling pathways regulate the proliferation, renewal, differentiation, invasion, metastasis, survival, and drug resistance of cancer stem cells.