Abstract
Increasing autophagy is beneficial for curing hepatocellular carcinoma (HCC). Damage-regulated autophagy modulator (DRAM) was recently reported to induce apoptosis by mediating autophagy. However, the effects of DRAM-mediated autophagy on apoptosis in HCC cells remain unclear. In this study, normal hepatocytes (7702) and HCC cell lines (HepG2, Hep3B and Huh7) were starved for 48 h. Starvation induced apoptosis and autophagy in all cell lines. We determined that starvation also induced DRAM expression and DRAM-mediated autophagy in both normal hepatocytes and HCC cells. However, DRAM-mediated autophagy was involved in apoptosis in normal hepatocytes but not in HCC cells, suggesting that DRAM-mediated autophagy fails to induce apoptosis in hepatoma in response to starvation. Immunoblot and immunofluorescence assays demonstrated that DRAM translocated to mitochondria and induced mitophagy, which led to apoptosis in 7702 cells. In HCC cells, starvation also activated the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which blocks the translocation of DRAM to mitochondria through the binding of p-AKT to DRAM in the cytoplasm. Inactivation of the PI3K/AKT pathway rescued DRAM translocation to mitochondria; subsequently, mitochondrial DRAM induced apoptosis in HCC cells by mediating mitophagy. Our findings open new avenues for the investigation of the mechanisms of DRAM-mediated autophagy and suggest that promoting DRAM-mediated autophagy together with PI3K/AKT inhibition might be more effective for autophagy-based therapy in hepatoma.
Highlights
P53 has been reported to induce damage-regulated autophagy modulator (DRAM)-mediated autophagy, which is a pro-apoptotic factor.[14] p73 has been identified to induce DRAM expression when p53 is deficient; p73-induced DRAM is not involved in the induction of autophagy and apoptosis.[15]
We determined that the effect of DRAM-mediated mitophagy on apoptosis is inhibited by activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in hepatoma cells in response to starvation
We believe that the finding that p-AKT binding to DRAM retards the translocation of DRAM to mitochondria is of considerable importance, as it links DRAM-mediated autophagic apoptosis to the PI3K/AKT pathway in hepatoma
Summary
P53 has been reported to induce DRAM-mediated autophagy, which is a pro-apoptotic factor.[14] p73 has been identified to induce DRAM expression when p53 is deficient; p73-induced DRAM is not involved in the induction of autophagy and apoptosis.[15]. The relationship between DRAM function and subcellular localization remains unclear, our previous study suggests that mitochondrial DRAM induces apoptosis in hepatoma cells by mediating mitophagy.[13] the effect of inducing DRAM-mediated autophagy in cancer cells has not been well studied until now. The anti-apoptotic activity caused by AKT activation has been suggested to depend on its translocation from the cytosol to the mitochondria, where it Received 09.7.13; revised 14.12.13; accepted 23.12.13; Edited by GM Fimia p-AKT inhibits apoptosis via binding DRAM in HCC K Liu et al inhibits opening of the permeability transition pore to maintain mitochondrial integrity.[22]. We used a normal liver cell line (7702) and three HCC cell lines (HepG2, Hep3B and Huh7) to detect the effect of DRAM-mediated autophagy on apoptosis induced by serum deprivation. We assessed whether DRAMmediated autophagy and the PI3K/AKT pathway engage in crosstalk that affects apoptosis
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