Oncogenic HSP60 regulates mitochondrial oxidative phosphorylation to support Erk1/2 activation during pancreatic cancer cell growth.
Oncogenic HSP60 regulates mitochondrial oxidative phosphorylation to support Erk1/2 activation during pancreatic cancer cell growth.
复制标题
致癌 HSP60 调节线粒体氧化磷酸化以支持胰腺癌细胞生长过程中 Erk1/2 的激活
DOI：
10.1038/s41419-017-0196-z
复制
发表时间：
2018-02-07
影响因子：
9
通讯作者：
Lyu J
中科院分区：
文献类型：
--
作者：
Zhou C;Sun H;Zheng C;Gao J;Fu Q;Hu N;Shao X;Zhou Y;Xiong J;Nie K;Zhou H;Shen L;Fang H;Lyu J
HSP60是一种线粒体定位的质控蛋白，负责维持线粒体功能。虽然HSP60被认为在不同类型的癌症中既是肿瘤抑制因子又是肿瘤启动子，但HSP60在人胰腺导管腺癌(PDAC)中的作用尚不清楚。在这项研究中，我们证明了HSP60在人胰腺癌组织和细胞系中异常表达。癌症基因组图谱数据库的分析显示，HSP60的表达与胰腺癌呈正相关。此外，HSP60基因敲除抑制了胰腺导管癌细胞的增殖和迁移/侵袭，而异位表达HSP60则增加了肿瘤的发生。通过体内致瘤性实验，我们证实了HSP60促进了胰腺导管癌细胞的生长。功能分析表明，HSP60在线粒体功能的调节中起着关键作用。在机制上，二甲双胍抑制HSP60和氧化磷酸化(OXPHOS)均可降低ERK1/2的磷酸化水平，并诱导细胞凋亡和细胞周期停滞，而EGF可使ERK1/2重新激活，促进细胞增殖。有趣的是，在体外，补充ATP部分恢复了PDAC细胞中ERK1/2的磷酸化，并促进了HSP60基因敲除和OXPHOS抑制的细胞增殖。这些结果表明，线粒体ATP是ERK1/2调控PDAC细胞凋亡和细胞周期的重要感受器。因此，我们的研究结果首次表明，HSP60可能是人类胰腺癌的一个新的诊断靶点，而使用二甲双胍等药物抑制线粒体功能可能是针对具有HSP60/OXPHOS/ERK1/2磷酸化轴异常功能的胰腺癌细胞的一种有益的治疗策略。
HSP60 is a mitochondrial localized quality control protein responsible for maintaining mitochondrial function. Although HSP60 is considered both a tumor suppressor and promoter in different types of cancer, the role of HSP60 in human pancreatic ductal adenocarcinoma (PDAC) remains unknown. In this study, we demonstrated that HSP60 was aberrantly expressed in human pancreatic cancer tissues and cell lines. Analysis of the Cancer Genome Atlas database revealed that HSP60 expression is positively correlated with pancreatic cancer. Further, knockdown of HSP60 attenuated pancreatic ductal cancer cell proliferation and migration/invasion, whereas ectopic expression of HSP60 increased tumorigenesis. Using an in vivo tumorigenicity assay, we confirmed that HSP60 promoted the growth of pancreatic ductal cancer cells. Functional analyses demonstrated that HSP60 plays a key role in the regulation of mitochondrial function. Mechanistically, both HSP60 knockdown and oxidative phosphorylation (OXPHOS) inhibition by metformin decreased Erk1/2 phosphorylation and induced apoptosis and cell cycle arrest, whereas Erk1/2 reactivation with EGF promoted cell proliferation. Intriguingly, in vitro ATP supplementation partially restored Erk1/2 phosphorylation and promoted proliferation in PDAC cells with HSP60 knockdown and OXPHOS inhibition. These results suggest that mitochondrial ATP is an important sensor of Erk1/2 regulated apoptosis and the cell cycle in PDAC cells. Thus, our findings indicate for the first time that HSP60 may serve as a novel diagnostic target of human pancreatic cancer, and that inhibition of mitochondrial function using drugs such as metformin may be a beneficial therapeutic strategy targeting pancreatic cancer cells with aberrant function of the HSP60/OXPHOS/Erk1/2 phosphorylation axis.
登录
查看更多内容
影响因子：
7.7
作者：
Märker T;Sell H;Zillessen P;Glöde A;Kriebel J;Ouwens DM;Pattyn P;Ruige J;Famulla S;Roden M;Eckel J;Habich C
通讯作者：
Habich C
影响因子：
4.5
作者：
Deng J;Yang M;Chen Y;Chen X;Liu J;Sun S;Cheng H;Li Y;Bigio EH;Mesulam M;Xu Q;Du S;Fushimi K;Zhu L;Wu JY
通讯作者：
Wu JY
DOI：
10.1083/jcb.200306132
发表时间：
2003-11-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kaufman BA;Kolesar JE;Perlman PS;Butow RA
通讯作者：
Butow RA
影响因子：
4.1
作者：
Abas, L;Bogoyevitch, MA;Guppy, M
通讯作者：
Guppy, M
影响因子：
4.3
作者：
Juwono J;Martinus RD
通讯作者：
Martinus RD