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

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          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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          Author and article information

          Journal
          Oncogene
          Oncogene
          1476-5594
          0950-9232
          May 7 2015
          : 34
          : 19
          Affiliations
          [1 ] Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, ROC.
          [2 ] Division of Thoracic Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, ROC.
          [3 ] 1] Division of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC [2] School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
          [4 ] 1] Division of Thoracic Surgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan, ROC [2] Department of Medicine, Tzu Chi University, Hualien, Taiwan, ROC.
          [5 ] Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC.
          Article
          onc2014184
          10.1038/onc.2014.184
          24998847

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