Author of

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  P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12473

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    P3.06-033 - Subcellular localization of Nrf2 promotes tumor aggressiveness, poor outcome, and unfavorable response to chemotherapy via increased IKKβ stability in NSCLC (ID 2514)

    09:30 - 09:30  |  Author(s): T. Wu
    • Abstract

    Background
    Dysfunction of Nrf2-Keap1 interaction by Keap1 or Nrf2 mutations may promote tumor growth, drug resistance, and poor outcomes in non-small cell lung cancer (NSCLC). However, both gene mutations are uncommon in Asian patients, suggesting that a different mechanism might be involved in lung tumor progression via altering Nrf2-Keap1 pathway.

    Methods
    Two strategies—treatment of NO scavenger and a nuclear location sequence (NLS)-mutated Nrf2 expression vector transfected into Nrf2-knockdown stable clones—were used to explore whether IKKβ could be elevated by cytoplasmic Nrf2 and promotes cell invasion. The prognostic values of cytoplasmic Nrf2 and IKKβ mRNA levels in tumors from NSCLC patients were estimated by Kaplan Meier and Cox regression model.

    Results
    We showed that mutated p53 upregulated Nrf2 transcription by de-repression of Sp1 binding to the Nrf2 promoter. Interestingly, cytoplasmic Nrf2 expression was markedly increased in p53-mutated cells compared with p53 wildtype cells due to a decrease in iNOS-mediated NO production. The stability of IKKβ protein was also increased by the interaction of cytoplasmic Nrf2 with Keap1, which blocked IKKβ degradation by the Keap1-mediated proteasomal pathway. An increase in IKKβ expression due to cytoplasmic Nrf2 was responsible for soft agar growth and invasion capability. Positive cytoplasmic Nrf2 immunostaining or high IKKβ mRNA expression in tumors from NSCLC patients may predict poorer overall survival and relapse free survival. Moreover, patients with cytoplasmic Nrf2 positive tumors had unfavorable responses to cisplatin-based chemotherapy.

    Conclusion
    Cytoplasmic Nrf2 may promote tumor aggressiveness, poor outcome, and unfavorable response to chemotherapy in NSCLC.