Phosphorylated AKT inhibits the apoptosis induced by DRAM-mediated mitophagy in hepatocellular carcinoma by preventing the translocation of DRAM to mitochondria.
Phosphorylated AKT inhibits the apoptosis induced by DRAM-mediated mitophagy in hepatocellular carcinoma by preventing the translocation of DRAM to mitochondria.
复制标题
磷酸化 AKT 通过阻止 DRAM 易位至线粒体来抑制肝细胞癌中 DRAM 介导的线粒体自噬诱导的细胞凋亡
DOI：
10.1038/cddis.2014.51
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发表时间：
2014-02-20
影响因子：
9
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中科院分区：
文献类型：
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增加自噬有利于肝细胞癌的治疗。损伤调节自噬调节剂(DRAM)最近被报道通过介导自噬来诱导细胞凋亡。然而，DRAM介导的自噬对肝癌细胞凋亡的影响尚不清楚。在本研究中，正常肝细胞(7702)和肝癌细胞系(HepG2、Hep3B和HuH7)被饥饿48h，饥饿诱导所有细胞系的凋亡和自噬。我们确定饥饿也诱导了正常肝细胞和肝癌细胞中DRAM的表达和DRAM介导的自噬。然而，DRAM介导的自噬参与了正常肝细胞的凋亡，而在肝癌细胞中则不参与，这表明DRAM介导的自噬不能诱导肝癌细胞在饥饿条件下发生凋亡。免疫印迹和免疫荧光分析表明，DRAM移位到线粒体并诱导有丝分裂，从而导致7702细胞的凋亡。在肝癌细胞中，饥饿还激活了磷脂酰肌醇3-激酶(PI3K)/AKT通路，该通路通过p-AKT与细胞质中的DRAM结合来阻止DRAM向线粒体的移位。PI3K/AKT通路的失活挽救了DRAM易位到线粒体；随后，线粒体DRAM通过介导有丝分裂诱导肝癌细胞凋亡。我们的发现为研究DRAM介导的自噬机制开辟了新的途径，并提示促进DRAM介导的自噬和抑制PI3K/AKT可能是基于自噬的肝癌治疗更有效的方法。
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.