PRECLINICAL REPORTSc-Jun N-terminal kinase mediates microtubule-depolymerizing agent-induced microtubule depolymerization and G2/M arrest in MCF-7 breast cancer cellsChen, Juana,b; Sun, Wei-Lianga; Wasylyk, Bohdanc; Wang, Yan-Pinga,b; Zheng, Honga,bAuthor Information aLaboratory of Tumor Molecular Diagnosis bState Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, People’s Republic of China cInstitut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale, Université Louis Pasteur, Illkirch, Cedex, France Juan Chen and Wei-Liang Sun contributed equally to this study. All supplementary digital content is available directly from the corresponding author. Correspondence to Dr Hong Zheng, PhD, Laboratory of Tumor Molecular Diagnosis, West China Hospital, West China Medical School, Sichuan University, No. 37 Guo-xue-xiang, Chengdu, P.R. China Tel: +86 28 8542 2973; fax: +86 28 8542 2685; e-mail: [email protected] Received January 21, 2011 Accepted August 9, 2011 Anti-Cancer Drugs: January 2012 - Volume 23 - Issue 1 - p 98-107 doi: 10.1097/CAD.0b013e32834bc978 Buy Metrics 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. © 2012 Lippincott Williams & Wilkins, Inc.