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

Oncogene volume 34, pages 2505–2515 (2015)Cite this article

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A Corrigendum to this article was published on 17 July 2017

A Corrigendum to this article was published on 16 July 2015

A Corrigendum to this article was published on 07 May 2015

This article has been updated

Abstract

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.

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Change history

  • 07 May 2015

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue

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Acknowledgements

This work was jointly supported by grants from the National Health Research Institute (NHRI96-TD-G-111-006; NHRI97-TD-G-111-006) and the National Science Council (100-2314-B-038-043-MY3) of Taiwan, ROC.

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Author notes

  1. D-W Wu and M-C Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC,

    D-W Wu, N-Y Hsu, Y-W Cheng & H Lee

  2. Division of Thoracic Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, ROC

    M-C Lee

  3. Division of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC,

    T-C Wu & Y-C Wang

  4. School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC,

    T-C Wu & Y-C Wang

  5. Division of Thoracic Surgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan, ROC

    J-Y Wu

  6. Department of Medicine, Tzu Chi University, Hualien, Taiwan, ROC,

    J-Y Wu

  7. Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC,

    C-Y Chen

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Wu, DW., Lee, MC., Hsu, NY. et al. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction. Oncogene 34, 2505–2515 (2015). https://doi.org/10.1038/onc.2014.184

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