Figure 5.

Regulatory mechanism of autophagy as determined by adiponectin and its different effects on cancer cell malignancy. Adiponectin deficiency reduces autophagy-related protein expression in primary tumor cells. A reduction in autophagy explains the increased cholesterol, LDL, and LDLR associated with accelerated tumor development in adiponectin deficiency conditions. This mechanism highlights autophagy as a possible pathway by which adiponectin deficiency might favor obesity-associated malignancies, especially breast cancer. On the other hand, supplying adiponectin has been proposed as a cancer therapy, particularly in obesity-associated cancer, since the addition of high levels of adiponectin to tumor cells induced autophagy and apoptosis. In this sense, it has been shown that adiponectin-induced autophagy negatively regulates apoptosis via the downregulation of Bax. Because autophagy inhibits adiponectin-induced apoptosis, it was suggested that the inhibition of autophagy would be an important therapeutic approach for enhancing the efficacy of cancer treatment with adiponectin. Additionally, it has been demonstrated that adiponectin-induced autophagy contributes to adiponectin-induced cancer cell death. Adiponectin inhibits ERK phosphorylation, which negatively regulates STK11/LKB1-AMPK activation. STK11/LKB1 leads to AMPK activation, which in turn increases ULK phosphorylation and induces autophagy. Adiponectin-induced autophagy was associated with the cleavage of PARP1 driven by adiponectin.