title: c-Jun N-terminal kinase mediates microtubule-depolymerizing agent-induced microtubule depolymerization and G2/M arrest in MCF-7 breast cancer cells.
abstract: Microtubule-binding agents (MBAs) form one of the most important anticancer-drug families, but their molecular mechanisms are poorly understood. MBAs such as paclitaxel (PTX) stabilize microtubules, whereas XRP44X (a novel pyrazole) and combretastatins A4 (CA4) destabilize microtubules. These two different types of MBAs have potent antitumor activity. Comparisons of their effects on signal transduction and cellular responses will help uncover the molecular mechanism by which MBAs affect tumor cells. We used MCF-7 cells to compare the effects of the three MBAs on the cytoskeleton, cell cycle distribution, and activation of the three major mitogen-activated protein kinase (MAPK) signaling cascades [extracellular signal-related kinases, c-Jun N-terminal kinase (JNK), and p38 MAPK] using pharmacological inhibitors. The G2/M phase arrest was induced following polymerization of microtubules by PTX and depolymerization by XRP44X and CA4. The three major MAPKs were rapidly activated by XRP44X, and extracellular signal-related kinases and p38 by PTX, whereas JNK did not quickly respond to PTX. Pharmacological inhibitors indicated that activation of JNK is principally required for XRP44X- and CA4-induced microtubule depolymerization and G2/M phase arrest. Our results suggest that early phosphorylation of JNK is a specific mechanism involved in microtubule depolymerization by certain MBAs.
authors.affiliation: Laboratory of Tumor Molecular Diagnosis, West China Hospital, West China Medical School, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Sun
authors.forename: Bohdan
authors.initials: B
authors.lastname: Wasylyk
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008870:Microtubules / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D005419:Flavonoids; D010879:Piperazines; D011720:Pyrazoles; D013267:Stilbenes; C527882:XRP44X compound; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C058728:fosbretabulin; D017239:Paclitaxel; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one