Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Clinical Laboratory, Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Cell Death Dis. 2018 Feb 7;9(2):161. doi: 10.1038/s41419-017-0196-z.
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.
HSP60 是一种定位于线粒体的质量控制蛋白，负责维持线粒体功能。虽然 HSP60 在不同类型的癌症中被认为既是肿瘤抑制因子又是促进因子，但它在人类胰腺导管腺癌（PDAC）中的作用尚不清楚。在这项研究中，我们证明 HSP60 在人类胰腺癌组织和细胞系中异常表达。对癌症基因组图谱数据库的分析表明，HSP60 的表达与胰腺癌呈正相关。进一步的研究表明，敲低 HSP60 可减弱胰腺导管癌细胞的增殖和迁移/侵袭能力，而过表达 HSP60 则增加肿瘤发生。通过体内肿瘤发生测定实验，我们证实 HSP60 促进了胰腺导管癌细胞的生长。功能分析表明，HSP60 在调节线粒体功能方面发挥着关键作用。在机制上，HSP60 的敲低和二甲双胍对氧化磷酸化（OXPHOS）的抑制均降低了 Erk1/2 的磷酸化，并诱导了细胞凋亡和细胞周期停滞，而用表皮生长因子（EGF）重新激活 Erk1/2 则促进了细胞增殖。有趣的是，体外补充 ATP 部分恢复了 Erk1/2 的磷酸化，并促进了 HSP60 敲低和 OXPHOS 抑制的 PDAC 细胞的增殖。这些结果表明，线粒体 ATP 是 Erk1/2 调控的 PDAC 细胞凋亡和细胞周期的重要传感器。因此，我们的研究结果首次表明，HSP60 可能作为人类胰腺癌的新型诊断靶点，而使用二甲双胍等药物抑制线粒体功能可能是针对 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。
