FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction

D. W. Wu, M. C. Lee, N. Y. Hsu, T. C. Wu, J. Y. Wu, Y. C. Wang, Y. W. Cheng, C. Y. Chen, H. Lee

研究成果: 雜誌貢獻文章

33 引文 斯高帕斯(Scopus)

摘要

Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor - perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome.
原文英語
頁(從 - 到)2505-2515
頁數11
期刊Oncogene
34
發行號19
DOIs
出版狀態已發佈 - 五月 7 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics
  • Medicine(all)

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    Wu, D. W., Lee, M. C., Hsu, N. Y., Wu, T. C., Wu, J. Y., Wang, Y. C., Cheng, Y. W., Chen, C. Y., & Lee, H. (2015). FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction. Oncogene, 34(19), 2505-2515. https://doi.org/10.1038/onc.2014.184