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Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell

Ashish Saxena1, Mohammad Shoeb, Kota V Ramana

  • 1Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, United States.

European Journal of Cancer (Oxford, England : 1990)
|July 6, 2013
PubMed

Insights

Inhibiting aldose reductase (AR) blocks growth factor-induced colon cancer. This occurs by reducing miR-21 and increasing programmed cell death 4 (PDCD4) via the ROS/AMPK/mTOR pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Aldose reductase (AR) inhibition shows promise in preventing colon cancer cell growth.
  • The precise role of AR in mediating growth factor-induced colon cancer proliferation remains unclear.

Purpose of the Study:

  • To investigate how AR inhibition impedes tumor growth.
  • To elucidate the mechanism involving microRNA-21 (miR-21) and programmed cell death 4 (PDCD4) expression in colon cancer.

Main Methods:

  • Utilized in vitro (HT29, SW480, Caco-2 cells) and in vivo (nude mice xenografts) models.
  • Administered epidermal growth factor (EGF) and AR inhibitor (fidarestat).
  • Assessed expression and phosphorylation levels of key proteins and microRNAs (miR-21, PDCD4, mTOR, AMPK, etc.).

Main Results:

  • AR inhibition prevented EGF-induced miR-21 upregulation and increased PDCD4 levels.
  • AR inhibition blocked EGF-induced phosphorylation of mTOR pathway components and increased AMPK phosphorylation.
  • In vivo studies confirmed increased PDCD4 and 4E-binding protein 1 (4E-BP1) in AR inhibitor-treated mice.

Conclusions:

  • AR inhibition effectively suppresses growth factor-driven colon cancer progression.
  • The mechanism involves down-regulation of miR-21 and upregulation of PDCD4 via the ROS/AMPK/mTOR/AP1/4E-BP1 signaling axis.
Keywords:
AMPKAldose reductaseColon cancerPDCD4miR-21

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