Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells.
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.
Wang
Xianghong
X
Cancer Biology Group, Department of Anatomy, Faculty of Medicine, University of Hong Kong, Hong Kong. xhwang@hkucc.hku.hk
Ling
Ming Tat
MT
Guan
Xin-Yuan
XY
Tsao
Sai Wah
SW
Cheung
Hiu Wing
HW
Lee
Davy Tak
DT
Wong
Yong Chuan
YC
D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1; D001749:Urinary Bladder Neoplasms / Q000235:genetics; D014750:Vincristine / Q000494:pharmacology
D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014750:Vincristine; D017239:Paclitaxel