Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells.
TWIST, a basic helix-loop-helix transcription factor, has been reported to be associated with development and progression of human cancer. Recently, over expression of TWIST is found in cancer patients with shorter survival and poor response to chemotherapy. Previously, we found that upregulation of TWIST was responsible for the development of acquired resistance to taxol in a nasopharyngeal carcinoma (NPC) cell line, HNE1-T3 (Wang et al., Oncogene, 2004;24:274). In this study, we investigated the underlying molecular mechanisms responsible for the TWIST-mediated taxol resistance. By comparison of the parental HNE1 and its derivative HNE1-T3 cell lines, we found that the resistance to taxol in HNE1-T3 cells was associated with suppression of taxol-induced apoptosis evidenced by decreased expression of Bak and Bax and increased Bcl-2, as well as inhibition of PARP and caspase cleavage and DNA ladder formation. However, there was no correlation between taxol sensitivity and alterations on G2/M cell cycle distribution, suggesting that the TWIST-induced taxol resistance is mediated through protection against apoptosis but not mitotic arrest. Analysis of additional 8 NPC cell lines showed that upregulation of TWIST was associated with resistance to microtubule disrupting agents, especially taxol, and inactivation of TWIST through small RNA interference led to increased sensitivity to taxol-induced cell death. Subsequent studies also demonstrated that the TWIST-mediated taxol resistance may be regulated through its positive involvement with the Akt pathway. Our findings suggest an underlying molecular mechanism responsible for the TWIST-mediated chemodrug resistance and suggest a target for overcoming taxol resistance in cancer cells.
Zhang
Xiaomeng
X
Cancer Biology Group, Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Wang
Qi
Q
Ling
Ming-Tat
MT
Wong
Yong Chuan
YC
Leung
Steve C L
SC
Wang
Xianghong
X
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000502:physiology*; D014750:Vincristine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000972:Antineoplastic Agents, Phytogenic; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D014750:Vincristine; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D017239:Paclitaxel