线粒体自噬蛋白PINK1抑制结肠癌的生长
  • 与正常大肠相比,人类结直肠癌(CRC)组织中PINK1表达下调;
  • 两种结肠炎相关CRC模型中,缺失PINK1增加结肠肿瘤生成;
  • 小鼠结肠癌细胞中过表达PINK1激活p53信号,促进有丝分裂吞噬和线粒体呼吸,减少糖酵解,而缺失PINK1则减少细胞凋亡和线粒体呼吸,增加糖酵解,p53信号;
  • PINK1过表达上调细胞凋亡,抑制小鼠中结肠癌生长,且肿瘤中乙酰-CoA显著降低,这与PDHK1-PDHE1α轴的激活部分相关;
  • PINK1缺失则促进肿瘤生长和乙酰-CoA的产生。
主编推荐语
爱的抉择
代谢的重编程是癌症的早期标志,线粒体产生的能量较少,糖酵解产生的能量增加。线粒体自噬蛋白PINK1是有丝分裂吞噬的关键调节因子,通过自噬选择性清除受损的线粒体。有丝分裂吞噬功能的缺陷与大肠癌等多种疾病具有相关性。Cell Death and Differentiation近期发表的文章,发现线粒体自噬蛋白PINK1是一种肿瘤抑制因子,可以调节细胞代谢,促进结直肠癌细胞死亡。机制上,PINK1通过激活p53和减少乙酰-CoA的产生,进行代谢重编程来抑制结肠肿瘤的发生。
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Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production

PINK1通过p53活化和减少乙酰辅酶a的产生进行代谢重编程,从而抑制结肠癌的生长

10.1038/s41418-021-00760-9

03-15, Article

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Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US. Understanding the mechanisms of CRC progression is essential to improve treatment. Mitochondria is the powerhouse for healthy cells. However, in tumor cells, less energy is produced by the mitochondria and metabolic reprogramming is an early hallmark of cancer. The metabolic differences between normal and cancer cells are being interrogated to uncover new therapeutic approaches. Mitochondria targeting PTEN-induced kinase 1 (PINK1) is a key regulator of mitophagy, the selective elimination of damaged mitochondria by autophagy. Defective mitophagy is increasingly associated with various diseases including CRC. However, a significant gap exists in our understanding of how PINK1-dependent mitophagy participates in the metabolic regulation of CRC. By mining Oncomine, we found that PINK1 expression was downregulated in human CRC tissues compared to normal colons. Moreover, disruption of PINK1 increased colon tumorigenesis in two colitis-associated CRC mouse models, suggesting that PINK1 functions as a tumor suppressor in CRC. PINK1 overexpression in murine colon tumor cells promoted mitophagy, decreased glycolysis and increased mitochondrial respiration potentially via activation of p53 signaling pathways. In contrast, PINK1 deletion decreased apoptosis, increased glycolysis, and reduced mitochondrial respiration and p53 signaling. Interestingly, PINK1 overexpression in vivo increased apoptotic cell death and suppressed colon tumor xenograft growth. Metabolomic analysis revealed that acetyl-CoA was significantly reduced in tumors with PINK1 overexpression, which was partly due to activation of the HIF-1α-pyruvate dehydrogenase (PDH) kinase 1 (PDHK1)-PDHE1α axis. Strikingly, treating mice with acetate increased acetyl-CoA levels and rescued PINK1-suppressed tumor growth. Importantly, PINK1 disruption simultaneously increased xenografted tumor growth and acetyl-CoA production. In conclusion, mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming and reducing acetyl-CoA production.

First Authors:
Kunlun Yin

Correspondence Authors:
Xiang Xue

All Authors:
Kunlun Yin,Jordan Lee,Zhaoli Liu,Hyeoncheol Kim,David R Martin,Dandan Wu,Meilian Liu,Xiang Xue

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