title: High dose of extracellular ATP switched autophagy to apoptosis in anchorage-dependent and anchorage-independent hepatoma cells.
abstract: Extracellular adenosine triphosphate (eATP) transduces purinergic signal and plays an important regulatory role in many biological processes, including tumor cell growth and cell death. A large amount of eATP exists in the fast-growing tumor center and inflammatory tumor microenvironment. Tumor cells could acquire anoikis resistance and anchorage independence in tumor microenvironment and further cause metastatic lesion. Whether such a high amount of eATP has any effect on the anchored and non-anchored tumor cells in tumor microenvironment has not been elucidated and is investigated in this study. Our data showed that autophagy helped hepatoma cells to maintain survival under the treatment of no more than 1 mM of eATP. Only when eATP concentration reached a relatively high level (2.5 mM), cell organelle could not be further maintained by autophagy, and apoptosis and cell death occurred. In hepatoma cells under treatment of 2.5 mM of eATP, an AMP-activated protein kinase (AMPK) pathway was dramatically activated while mTOR signaling pathway was suppressed in coordination with apoptosis. Further investigation showed that the AMPK/mTOR axis played a key role in tipping the balance between autophagy-mediated cell survival and apoptosis-induced cell death under the treatment of eATP. This work provides evidence to explain how hepatoma cells escape from eATP-induced cytotoxicity as well as offers an important clue to consider effective manipulation of cancer.
authors.affiliation: Department of Immunology, Shandong Provincial Key Laboratory of Infection & Immunology, School of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wei
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Jia
authors.forename: Wanwan
authors.initials: W
authors.lastname: Huai
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Yu
authors.forename: Zhengkun
authors.initials: Z
authors.lastname: Wan
authors.forename: Lihui
authors.initials: L
authors.lastname: Han
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000378:metabolism*; D006801:Humans; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000255:Adenosine Triphosphate