title: B1-induced caspase-independent apoptosis in MCF-7 cells is mediated by down-regulation of Bcl-2 via p53 binding to P2 promoter TATA box.
abstract: The Bcl-2 family contains a panel of proteins which are conserved regulators of apoptosis in mammalian cells, like the anti-apoptotic protein Bcl-2. According to its significant role in altering susceptibility to apoptosis, the deciphering of the mechanism of Bcl-2 expression modulation may be crucial for identifying therapeutics strategies for cancer. Treatment with naphthalimide-based DNA intercalators, including M2-A and R16, generally leads to a decrease in Bcl-2 intracellular amounts. Whereas the interest for these chemotherapeutics is accompanied by advances in the fundamental understanding of their anticancer properties, the molecular mechanism underlying changes in Bcl-2 expression remains poorly understood. We report here that p53 contributes to Bcl-2 down-regulation induced by B1, a novel naphthalimide-based DNA intercalating agent. Indeed, the decrease in Bcl-2 protein levels observed during B1-induced apoptosis was correlated to the decrease in mRNA levels, as a result of the inhibition of Bcl-2 transcription and promoter activity. In this context, we evaluated p53 contribution in the Bcl-2 transcriptional down-regulation. We found a significant increase of p53 binding to P(2) promoter TATA box in MCF7 cells by chromatin immunoprecipitation. These data suggest that B1-induced caspase-independent apoptosis in MCF-7 cells is associated with the activation of p53 and the down-regulation of Bcl-2. Our study strengthens the links between p53 and Bcl-2 at a transcriptional level, upon naphthalimide-based DNA intercalator treatment.
authors.affiliation: State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, #268, 130 Meilong Road, Shanghai 200237, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018996:Myelin P2 Protein / Q000378:metabolism*; D053644:Naphthalimides / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016385:TATA Box / Q000187:drug effects* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007364:Intercalating Agents; D018996:Myelin P2 Protein; D053644:Naphthalimides; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D020169:Caspases