Methyl methanesulfonate induces apoptosis in p53-deficient H1299 and Hep3B cells through a caspase 2- and mitochondria-associated pathway |
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| Affiliation: | 1. Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China;2. Department of Pharmaceutical Laboratory, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu Province, China;3. Department of Pathology, Medical College of Soochow University, Suzhou 215123, Jiangsu Province, China;1. Jiangsu Key Laboratory for Biodiversity & Biotechnology and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210046, China;2. College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei 430070, China;3. Freshwater Fisheries Research Institute of Jiangsu Province, 79 Chating East Street, Nanjing 210017, China;1. Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, 2# Fuxue Road, Wenzhou 325027, People''s Republic of China;2. The Department of Spinal Surgery, Second Affiliated Hospital of Wenzhou Medical University, Zhejiang Spinal Research Center, 109# XueYuan Western Road, Wenzhou, Zhejiang 325027, People''s Republic of China |
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| Abstract: | Methyl methanesulfonate (MMS) has been shown to induce apoptosis in various cell types through p53-dependent pathways. Nevertheless, pharmacological and genetic blockade of p53 functions results in similar or delayed sensitivity to MMS treatment, suggesting the presence of p53-independent apoptotic mechanisms. To understand the p53-independent mechanisms that are engaged during MMS-induced apoptosis, we established MMS-induced apoptotic cell models using p53-deficient H1299 and Hep3B cells. Our results demonstrated that MMS at concentrations of 50, 100, 200, 400 and 800 μM induced the formation of gammaH2AX foci, and that at higher concentrations, 400 and 800 μM, MMS treatment led to apoptosis in the two cell lines. This apoptotic cell death was concurrent with the loss of mitochondrial membrane potential, nuclear-cytosolic translocation of active caspase 2, release of cytochrome c from mitochondria, and the cleavage of caspase 9, caspase 3 and PARP. However, MMS-induced DNA damage failed to stabilize the p53 family members TAp73 and DNp73. These results demonstrated a p53- and p73-independent mechanism for MMS-induced apoptosis that involves the nuclear-cytosolic translocation of active caspase 2 as well as the mitochondria-mediated pathway. |
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