Tubulozole-induced G2/M cell cycle arrest in human colon cancer cells through formation of microtubule polymerization mediated by ERK1/2 and Chk1 kinase activation

  • Food Chem Toxicol. 2007 Aug;45(8):1356-67. doi: 10.1016/j.fct.2007.01.012.
Yean-Hwei Chou  1 ,  Yuan-Soon Ho ,  Chi-Chen Wu ,  Chiah-Yang Chai ,  Soul-Chin Chen ,  Chia-Hwa Lee ,  Pei-Shan Tsai ,  Chih-Hsiung Wu
Affiliations
  • 1. Department of Surgery, Division of General Surgery, School of Medicine, Taipei Medical University and Hospital, No. 252 Wu-Hsing Street, Taipei 110, Taiwan.
PMID: 17329004 DOI: 10.1016/j.fct.2007.01.012
Abstract

Our studies demonstrated that human colon Cancer cells (COLO 205), with higher expression level of check point kinase 1 (Chk1), were more sensitive to microtubule damage agent Tubulozole (TUBU) induced G2/M phase arrest than normal human colon epithelial (CRL) cells. TUBU (10 microM, for 3h) treatment resulted in rapid and sustained phosphorylation of Cdc25C (Ser-216) leading to increased 14-3-3beta binding. This resulted in increased nuclear translocation. In addition, TUBU induced phosphorylation of the Cdc25C (Ser-216) and Bad (Ser-155) proteins were blocked by Chk1 SiRNA-transfection. Surprisingly, cellular apotosis was observed in cells treated with TUBU after Chk1 SiRNA inhibition. We further demonstrated that extracellular signal-regulated kinase (ERK) activation by TUBU was needed for Chk1 kinase activation and microtubule formation as shown by the attenuation of these responses by the ERK1/2 specific inhibitor PD98059. However, TUBU induced ERK1/2 phosphorylation was not blocked in the Chk1 SiRNA-transfected COLO 205 cells. These results imply that ERK1/2 mediated Chk1 activation may be play an important role in determining TUBU induced G2/M arrest or Apoptosis in COLO 205 cells.

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