Involvement of mitophagy in oncogenic K-Ras-induced transformation Overcoming a cellular energy deficit from glucose deficiency
Involvement of mitophagy in oncogenic K-Ras-induced transformation Overcoming a cellular energy deficit from glucose deficiency
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DOI：
10.4161/auto.7.10.16643
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发表时间：
2011-10-01
期刊：
影响因子：
13.3
通讯作者：
Yoon, Gyesoon
中科院分区：
文献类型：
--
作者：
Kim, June-Hyung;Kim, Hee Young;Yoon, Gyesoon
虽然线粒体损伤经常与癌症的发生有关，但其在癌症中发展的机制仍不清楚。我们在这里报道，致癌K-RAS引发的自噬在细胞转化过程中介导了线粒体功能的丧失，以克服葡萄糖缺乏引起的能量短缺。当Rat2细胞感染含有固有活性K-RAS(V12)的逆转录病毒时，线粒体呼吸显著下降，同时获得转化特征。呼吸减少与线粒体的生物发生无关，而与包裹线粒体的酸性小泡的形成呈负相关，在此过程中，自噬相关蛋白Beclin 1、ATG5、LC3-II和空泡ATPase被诱导。有趣的是，用传统的抑制剂(巴菲洛霉素A，3-甲基腺苷)阻断自噬和siRNA介导的自噬相关基因的敲除可以恢复呼吸蛋白的表达和呼吸活性；JNK作为上游调节因子参与了这些现象。K-RAS(V12)转化的细胞主要通过糖酵解产生ATP而不诱导低K-m葡萄糖转运蛋白GLUT1，从而维持细胞内的ATP水平。最后，K-RAS(V12)触发的LC3-II的形成受细胞外葡萄糖水平的调节，并且只有在表现为低葡萄糖摄取和K-RAS表达增加的肝细胞癌组织中，LC3-II的形成才会增加。综上所述，我们的观察表明，即使在没有缺氧的情况下，线粒体功能的丧失也可能是由致癌K-RAS诱导的早期肿瘤发生中的有丝分裂所介导的，并且这一有丝分裂过程可能是克服葡萄糖不足引发的细胞能量不足的重要策略。
Although mitochondrial impairment has often been implicated in carcinogenesis, the mechanisms of its development in cancer remain unknown. We report here that autophagy triggered by oncogenic K-Ras mediates functional loss of mitochondria during cell transformation to overcome an energy deficit resulting from glucose deficiency. When Rat2 cells were infected with a retrovirus harboring constitutively active K-Ras(V12), mitochondrial respiration significantly declined in parallel with the acquisition of transformation characteristics. Decreased respiration was not related to mitochondrial biogenesis but was inversely associated with the increased formation of acidic vesicles enclosing mitochondria, during which autophagy-related proteins such as Beclin 1, Atg5, LC3-II and vacuolar ATPases were induced. Interestingly, blocking autophagy with conventional inhibitors (bafilomycin A, 3-methyladenin) and siRNA-mediated knockdown of autophagy-related genes recovered respiratory protein expression and respiratory activity; JNK was involved in these phenomena as an upstream regulator. The cells transformed by K-Ras(V12) maintained cellular ATP level mainly through glycolytic ATP production without induction of GLUT1, the low K-m glucose transporter. Finally, K-Ras(V12)-triggered LC3-II formation was modulated by extracellular glucose levels, and LC3-II formation increased only in hepatocellular carcinoma tissues exhibiting low glucose uptake and increased K-Ras expression. Taken together, our observations suggest that mitochondrial functional loss may be mediated by oncogenic K-Ras-induced mitophagy during early tumorigenesis even in the absence of hypoxia, and that this mitophagic process may be an important strategy to overcome the cellular energy deficit triggered by insufficient glucose.