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The role of Nrf2 and ATF2 in resistance to platinum-based chemotherapy

Jianli Chen1,2, Charalambos Solomides3, Fiona Simpkins4

  • 1The Feinstein Institute for Medical Research, NS-LIJ Health System, 350 Community Drive, Manhasset, NY, 11030, USA.

Cancer Chemotherapy and Pharmacology
|January 26, 2017
PubMed
Abstract

Insights

Nuclear factor erythroid 2-related factor 2 (Nrf2) modulates platinum chemotherapy resistance by controlling aldo-keto reductases (AKR). Nrf2 knockdown increased reactive oxygen species (ROS) production and altered cell signaling pathways, impacting drug resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating cellular responses to oxidative stress.
  • Aldo-keto reductases (AKR) are enzymes implicated in chemoresistance, particularly to platinum-based agents.
  • Understanding Nrf2's role in AKR regulation is crucial for overcoming platinum resistance in cancer therapy.

Purpose of the Study:

  • To investigate the role of Nrf2 in regulating AKR family members.
  • To determine Nrf2's contribution to platinum-based chemotherapy resistance in various cancer cell lines.
  • To elucidate the molecular mechanisms underlying Nrf2-mediated chemoresistance.

Main Methods:

  • Nrf2 knockdown was achieved using shRNA in ovarian, cervical, and lung cancer cell lines.
  • Expression levels of AKR family members (AKR1C1, AKR1C2, AKR1C3) and other candidate genes were analyzed.
  • Cellular responses, including mitochondrial membrane depolarization, reactive oxygen species (ROS) production, and signaling pathway activation (pJNK/p38, ATF2), were assessed following platinum drug treatment.

Main Results:

  • Nrf2 knockdown significantly decreased AKR1C1, AKR1C2, and AKR1C3 expression.
  • Nrf2-deficient cells showed increased ROS production and mitochondrial depolarization upon cisplatin treatment.
  • Activation of the pJNK/p38 pathway and ATF2 phosphorylation were modulated by Nrf2 knockdown and platinum drugs.

Conclusions:

  • Nrf2 plays a significant role in modulating cisplatin resistance, primarily through the regulation of the AKR gene family.
  • Reactive oxygen species (ROS) production and the pJNK/p38 signaling pathway, involving ATF2, are key components of Nrf2-mediated chemoresistance.
  • These findings highlight Nrf2 as a potential therapeutic target for enhancing platinum-based chemotherapy efficacy.
Keywords:
ATF2CisplatinDrug resistanceLung, Cervical, Ovarian CancerNrf2Oxaliplatin

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