Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells
| Autor: | Sai Wah Tsao, Xianghong Wang, Hiu Wing Cheung, Xin Yuan Guan, Yong-Chuan Wong, Davy T. Lee, Ming-Tat Ling |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Cancer Research Paclitaxel Nasopharyngeal neoplasm Drug resistance Biology medicine.disease_cause Inhibitory Concentration 50 Twist transcription factor Downregulation and upregulation Tumor Cells Cultured Genetics medicine Humans Nuclear protein Molecular Biology Ovarian Neoplasms Helix-Loop-Helix Motifs Twist-Related Protein 1 Gene Amplification Nuclear Proteins Prostatic Neoplasms Cancer Nasopharyngeal Neoplasms medicine.disease Gene Expression Regulation Neoplastic Urinary Bladder Neoplasms Drug Resistance Neoplasm Vincristine Cancer research Female Ectopic expression Carcinogenesis Transcription Factors |
| Zdroj: | Oncogene. 23:474-482 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1207128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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