Modulation of cell-cycle regulatory signaling network by 2-methoxyestradiol in prostate cancer cells is mediated through multiple signal transduction pathways.
2-Methoxyestradiol (2-ME(2)), a promising anticancer drug, induces growth arrest and apoptosis in various androgen-dependent (LNCaP) and -independent (DU145 and PC-3) prostate cancer cell lines. Moreover, flow cytometric analysis indicated a novel dual impact of 2-ME(2) on the cell division cycle of prostate cancer cells. Chronic exposure of high doses of 2-ME(2) enhance the accumulation of cells in S and G2/M phases, while cell numbers in the G1 phase were reduced significantly by this treatment. Because cyclin B1 overexpression, induction of cdc2 phosphorylation, and its regulatory proteins wee1 and phospho-cdc25C (interphase and mitotic forms) by 2-ME(2) treatment correlated with the induction of apoptosis, growth arrest at the G2/M phase, and accumulation of the S phase, we reasoned that cyclin B1 and cdc2 phosphorylation and its upstream regulatory molecular networks may be associated with the ultimate impacts of 2-ME(2). Because phosphorylation of cdc2 and upregulation of wee1 by 2-ME(2) can be abolished by both extracellular receptor kinase (ERK) inhibitor (U0126) and c-Jun N-terminal kinase (JNK) inhibitor (SP600125), our studies indicate that the 2-ME(2)-induced upregulation of wee1 and subsequent cdc2 phosphorylation are mediated through mitogen-activated protein kinase (MAPK)-ERK-JNK signaling pathways.
Cancer Research Unit, Veterans Affairs Medical Center, Kansas City, Missouri, USA.
Gibanananda
G
Ray
Gopal
G
Dhar
Peter J
PJ
Van Veldhuizen
Snigdha
S
Banerjee
Neela K
NK
Saxena
Krishanu
K
Sengupta
Sushanta K
SK
Banerjee
D000077584:2-Methoxyestradiol; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D003593:Cytoplasm / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction; D050257:Tubulin Modulators / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000378:metabolism
C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D009687:Nuclear Proteins; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases