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Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in

Hyun Joo Jang1, Eun Mi Hong1, Mikang Kim1

  • 1Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred Heart Hospital, Hallym University School of Medicine, Gyeonggi do, Korea.

Oncotarget
|June 22, 2016
PubMed

Insights

Simvastatin activates the Nrf2 (NF-E2-related factor 2) pathway in colon cancer cells, increasing antioxidant enzymes via ERK and PI3K/Akt signaling. This highlights statins

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Statins possess pleiotropic effects beyond cholesterol reduction, including anti-inflammatory, antioxidant, and anti-cancer properties.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating cellular antioxidant responses to oxidative stress.
  • The impact of statins on Nrf2 activation and its signaling pathway in colon cancer remains largely unexplored.

Purpose of the Study:

  • To investigate whether simvastatin stimulates Nrf2 expression and nuclear translocation in colon cancer cells.
  • To identify the signaling pathways (ERK, PI3K/Akt) involved in simvastatin-induced Nrf2 activation.
  • To determine if simvastatin induces the expression of antioxidant enzymes.

Main Methods:

  • Utilized human colon cancer cell lines (HT-29, HCT 116).
  • Performed cell proliferation assays, Western blotting, and immunocytochemical analysis to assess Nrf2 expression and localization.
  • Employed PI3K/Akt inhibitor (LY294002) and ERK inhibitor (PD98059) to elucidate signaling pathways.

Main Results:

  • Simvastatin demonstrated a dose-dependent upregulation of Nrf2 expression and stimulated its nuclear translocation in colon cancer cells.
  • Simvastatin treatment led to the induction of key antioxidant enzymes: heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1 (NQO1), and γ-glutamate-cysteine ligase catalytic subunit (GCLC).
  • Inhibition of PI3K/Akt and ERK pathways suppressed simvastatin-induced Nrf2 and HO-1 expression, indicating their crucial role.

Conclusions:

  • Simvastatin effectively induces Nrf2 activation and nuclear translocation in colon cancer cells.
  • The activation of Nrf2 and subsequent expression of antioxidant enzymes by simvastatin are mediated through both ERK and PI3K/Akt signaling pathways.
  • These findings suggest a potential role for simvastatin in modulating oxidative stress responses within colon cancer, warranting further investigation.
Keywords:
NF-E2-related factorcolon cancerextracellular-signal-regulated kinaseheme oxygenase-1statin

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