2013 Fiscal Year Final Research Report

Resistance mechanisms for anti-tubulin agents in malignant melanomas

Research Project

Project/Area Number	24791171
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Dermatology
Research Institution	Iwate Medical University
Principal Investigator	AKASAKA K 岩手医科大学, 医学部, 研究員 (90552753)
Project Period (FY)	2012-04-01 – 2014-03-31
Keywords	悪性黒色腫 / BCL2 / BCLxL / 抗微小管薬
Research Abstract	Previous studies have suggested a link between TUBB3 overexpression and paclitaxel resistance through alterations in the properties of the mitotic spindle. We found that paclitaxel treatment induced temporary mitotic arrest in 7 melanoma cell lines irrespective of the TUBB3 level, suggesting that TUBB3 had no significant influence on spindle properties. On the other hand, the amount of BCL2, an anti-apoptotic protein, was well correlated with paclitaxel resistance. Treatment of the paclitaxel-resistant cell lines with ABT-737, an inhibitor of BCL2 and BCLxL, or simultaneous knock-down of BCL2 and BCLxL dramatically increased the cells' sensitivity, while knock-down of MCL1, another member of the BCL2 family, had only a minimal effect. Our results suggest that the paclitaxel sensitivity of melanoma cells is attributable to apoptosis susceptibility rather than a change in spindle properties and that BCL2 and BCLxL play a pivotal role in the former.