cancer cells acquire mitotic drug resistance properties through beta i-tubulin mutations and alterations in the expression of beta-tubulin isotypes肿瘤细胞耐药性获得有丝分裂属性通过βi-tubulin突变和改变的表达beta-tubulin同形像.pdfVIP

Cancer Cells Acquire Mitotic Drug Resistance Properties Through Beta I-Tubulin Mutations and Alterations in the Expression of Beta-Tubulin Isotypes 1 2 1 1 2 Chun Hei Antonio Cheung , Su-Ying Wu , Tian-Ren Lee , Chi-Yen Chang , Jian-Sung Wu , Hsing-Pang Hsieh2, Jang-Yang Chang1,3* 1 National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China, 2 Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes (NHRI), Zhunan, Taiwan, Republic of China, 3 Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China Abstract Background: Anti-mitotic compounds (microtubule de-stabilizers) such as vincristine and vinblastine have been shown clinically successful in treating various cancers. However, development of drug-resistance cells limits their efficacies in clinical situations. Therefore, experiments were performed to determine possible drug resistance mechanisms related to the application of anti-mitotic cancer therapy. Principal Findings: A KB-derived microtubule de-stabilizer-resistant KB-L30 cancer cell line was generated for this study. KB- L30 cells showed cross-resistance to various microtubule de-stabilizers including BPR0L075, vincristine and colchicine through multiple-drug resistant (MDR)-independent mechanisms. Surprisingly, KB-L30 cells showed hyper-sensitivity to the microtubule-stabilizer, paclitaxel. Results of the RT-PCR analysis revealed that expression of both class II and III b-tubulin was down-regulated in KB-L30 cells as compared to its parental KB cancer cells. In addition, DNA sequencing analysis revealed six