Wang Xianghong, Ling Ming Tat, Guan Xin-Yuan, Tsao Sai Wah, Cheung Hiu Wing, Lee Davy Tak, Wong Yong Chuan
Cancer Biology Group, Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong.
Oncogene. 2004 Jan 15;23(2):474-82. doi: 10.1038/sj.onc.1207128.
Taxol is one of the widely used chemotherapeutic drugs against many types of human cancer. While it is considered as one of the most effective anticancer drugs, treatment failure often occurs due to development of acquired resistance. Therefore, it is important to understand the molecular mechanisms responsible for the development of drug resistance. Although it is generally believed that taxol induces cell death through interfering with microtubules leading to mitotic arrest, recent evidence has suggested that taxol-induced cell death also occurs through pathways independent of either microtubule or mitotic arrest. In this study, we report the identification of a novel role for TWIST, a basic helix-loop-helix protein, which plays a central role in cell type determination and differentiation, during generation of acquired resistance to taxol in a nasopharyngeal carcinoma cell line, HNE1-T3, using comparative genome hybridization (CGH) and subsequent RT-PCR and Western blotting. We found that upregulation of TWIST was associated with cellular resistance to taxol but not other drugs with different mechanisms of action. The fact that increased TWIST protein levels were also associated with another microtubule-targeting anticancer drug, vincristine, in four types of human cancer including nasopharyngeal, bladder, ovarian and prostate, indicates that it may play a central role in the resistance to microtubule-disrupting agents. In addition, ectopic expression of TWIST into human cancer cells also led to increased resistance to both taxol and vincristine. Our results indicate a novel mechanism that leads to resistance to microtubule-disrupting anticancer drugs through upregulation of TWIST. Our evidence provides a therapeutic strategy to overcome acquired resistance through inactivation of TWIST expression in human cancer.
紫杉醇是广泛用于治疗多种人类癌症的化疗药物之一。虽然它被认为是最有效的抗癌药物之一，但由于获得性耐药的产生，治疗失败的情况经常发生。因此，了解导致耐药性产生的分子机制很重要。尽管人们普遍认为紫杉醇通过干扰微管导致有丝分裂停滞来诱导细胞死亡，但最近的证据表明，紫杉醇诱导的细胞死亡也通过独立于微管或有丝分裂停滞的途径发生。在本研究中，我们报告了利用比较基因组杂交（CGH）以及随后的逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹法，在鼻咽癌细胞系HNE1-T3中鉴定出一种新型碱性螺旋-环-螺旋蛋白TWIST在获得性紫杉醇耐药产生过程中的作用。TWIST在细胞类型确定和分化中起核心作用。我们发现TWIST的上调与细胞对紫杉醇的耐药性相关，但与其他作用机制不同的药物无关。在包括鼻咽癌、膀胱癌、卵巢癌和前列腺癌在内的四种人类癌症中，TWIST蛋白水平的升高也与另一种微管靶向抗癌药物长春新碱相关，这表明它可能在对微管破坏剂的耐药性中起核心作用。此外，将TWIST异位表达于人癌细胞中也导致对紫杉醇和长春新碱的耐药性增加。我们的结果表明了一种通过上调TWIST导致对微管破坏抗癌药物产生耐药性的新机制。我们的证据提供了一种通过使人类癌症中TWIST表达失活来克服获得性耐药的治疗策略。
