title: Down-regulation of cyclin E expression by caffeine promotes cancer cell entry into the S-phase of the cell cycle.
abstract: Expression of cyclin E is believed to be a critical factor promoting cell entry into the S-phase and cell proliferation. Indeed, normal proliferating cells and most tumor cell lines are characterized by the existence of a minimal cyclin E threshold level in the G1-phase, and only those cells expressing cyclin E over this threshold enter into the S-phase of the cell cycle. However, through studying clinical tumor tissue specimens, we recently observed that some cancer cells can enter into the S-phase with minimal levels of cyclin E expression. In an effort to establish an in vitro cell model system for studying the mechanisms underlying this phenomenon, we treated MOLT-4 lymphocyte leukemia cells with 50 mM caffeine and found that the levels of cyclin E expression were decreased markedly in these cells following 2 to 4-h exposure to caffeine. Quite unexpectedly, we observed that the percentage of the cells progressing through the S-phase increased despite the reduced levels of cyclin E, as analyzed for the cellular DNA contents, expression of nuclear-bound PCNA, immunolabelling with Ki-67 antibody and incorporation of BrdU. In fact, these cells entered into the S-phase with a level of cyclin E well below the threshold level for untreated cells, thus suggesting that lower levels of cyclin E expression are associated with cell proliferation under certain circumstances. We speculate that caffeine may enhance MOLT-4 cell entrance into the S-phase through activation of Cdc25, which in turn activates cyclin-dependent protein kinases (CDKs) including CDK2 and drives the cell cycle progression; while degradation of cyclin E by the ubiquitin/proteasome pathway may account for the decreased levels of cyclin E in these cells. Our findings from both the MOLT-4 cell line and patients' cancer tissues may help decipher the mystery of the deregulation of cell cycle progression and carcinogenesis in some malignant tumors.
authors.affiliation: Institute of Cancer Research and Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Jichao
authors.initials: J
authors.lastname: Qin
authors.forename: Deding
authors.initials: D
authors.lastname: Tao
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Chen
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Feng
authors.forename: Junbo
authors.initials: J
authors.lastname: Hu
authors.forename: Eddie
authors.initials: E
authors.lastname: Reed
authors.forename: Qingdi Q
authors.initials: QQ
authors.lastname: Li
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
mesh_terms: D002110:Caffeine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016196:S Phase / Q000187:drug effects* / Q000235:genetics
chemical_list: D019927:Cyclin E; D004273:DNA, Neoplasm; D002110:Caffeine