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Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity

C H Switzer1, L A Ridnour, R Y S Cheng

  • 1Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Oncogene
|August 25, 2009
PubMed

Insights

The dithiolethione compound ACS-1 inhibits cancer cell growth by increasing tumor suppressor protein phosphatase 2A (PP2A) activity. This mechanism is independent of antioxidant response element activation, suggesting broader therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Pharmacology
  • Biochemistry

Background:

  • Dithiolethione compounds are known for chemopreventive effects via antioxidant response element (ARE) activation.
  • The Nrf2/Keap1 protein complex is a key mediator in the cellular response to oxidative stress.
  • Understanding novel mechanisms of action for chemopreventive agents is crucial for cancer therapy development.

Purpose of the Study:

  • To investigate the antiproliferative effects of the dithiolethione compound ACS-1 in human cancer cell lines.
  • To elucidate the molecular mechanisms underlying ACS-1's anti-proliferative activity, focusing on protein phosphatase 2A (PP2A) and Akt signaling.
  • To determine if ACS-1's effects are linked to ARE activation.

Main Methods:

  • Utilized human cancer cell lines (A549 and MDA-MB-231) to assess ACS-1's antiproliferative effects.
  • Measured epidermal growth factor (EGF)-induced cellular proliferation, Akt activation (serine-473 phosphorylation), mammalian target of rapamycin (mTOR) signaling, and c-myc protein levels.
  • Assessed the role of PP2A by using the inhibitor okadaic acid and investigated the involvement of ARE activation and cAMP formation.

Main Results:

  • ACS-1 demonstrated concentration- and time-dependent inhibition of EGF-induced proliferation in cancer cells.
  • ACS-1 inhibited Akt activation and mTOR signaling while decreasing c-myc protein levels.
  • ACS-1 significantly increased PP2A activity in a concentration-dependent manner, an effect not dependent on ARE activation or cAMP formation.
  • The antiproliferative effect of ACS-1 on Akt activation was reversed by the PP2A inhibitor okadaic acid.

Conclusions:

  • The dithiolethione compound ACS-1 exhibits antiproliferative effects in human cancer cells by enhancing PP2A activity.
  • ACS-1's mechanism involves the inhibition of Akt and mTOR signaling pathways, independent of ARE activation.
  • These findings suggest that dithiolethione compounds, including ACS-1, may possess therapeutic potential beyond traditional chemoprevention.

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