Figure 1 Autophagy induction decreases tumor size and metastasis in clear cell renal cell tumors either through AMPK/mTOR-dependent or AMPK/mTOR-independent pathways. This might be related to a heterogeneous population of the tumor specimens. (A) AMPK/mTOR-dependent autophagy. mTOR negatively regulates autophagy by inhibiting the autophagy initiation complex, ULK complex. When the ATP/AMP ratio is low, AMPK activates the TSC complex by phosphorylation leading to mTOR inhibition and relief of the inhibitory effect of mTOR on the ULK complex. Alternatively, AMPK can also directly activate the ULK complex. Activation of ULK triggers the hierarchical activation autophagy machinery including class III PI3K complex I, consisting of BECLIN1 and hVPS34 proteins, ATG12-ATG5-ATG16L and phosphatidylethanolamine (PE) conjugated LC3 (LC3II). (B) AMPK/mTOR-independent autophagy. TRAF6 enhances ULK activity through ULK1 ubiquitination (Ub). The JNK pathway can directly activate BECLIN1. Also, DAPK1 can inhibit Bcl2, the inhibitory partner of BECLIN1. Activation of BECLIN1 triggers activation of class III PI3K complex I and therefore autophagy initiation, independent of the AMPK/mTOR pathway. AMPK, 5'-adenosine monophosphate-activated protein kinase; DAPK, death associated protein kinase 1; JNK, c-Jun N-terminal kinase; mTOR, mechanistic target of rapamycin; TRAF6, tumor necrosis factor receptor-associated factor 6; TSC, tuberous sclerosis complex; ULK, uncoordinated protein 51-like kinase. (The scheme was prepared by BioRender software).