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

Switzer CH, Ridnour LA, Cheng RY, Sparatore A, Del Soldato P, Moody TW, Vitek MP, Roberts DD, Wink DA - Oncogene (2009)

Bottom Line: The effect of ACS-1 on Akt activation was not observed in the presence of the PP2A inhibitor okadaic acid.ACS-1 effects on PP2A activity were independent of ARE activation and cAMP formation.In addition to ACS-1, other dithiolethione compounds showed similar effects in reducing Akt activation, suggesting that this class of compounds may have other effects beyond chemoprevention.

View Article: PubMed Central - PubMed

Affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
The chemopreventative effects of dithiolethione compounds are attributed to their activation of antioxidant response elements (AREs) by reacting with the Nrf2/Keap1 protein complex. In this study, we show antiproliferative effects of the dithiolethione compound ACS-1 in human cancer cell lines (A549 and MDA-MB-231) by increasing the activity of the tumor suppressor protein phoshatase 2A (PP2A). ACS-1 inhibited epidermal growth factor (EGF)-induced cellular proliferation in a concentration- and time-dependent manner. Akt activation, as determined by serine-473 phosphorylation, was inhibited by ACS-1 in cells stimulated with either EGF or fibronectin. Furthermore, ACS-1 inhibited mammalian target of rapamycin signaling and decreased c-myc protein levels. ACS-1 did not proximally alter EGF receptor or integrin signaling, but caused a concentration-dependent increase in PP2A activity. The effect of ACS-1 on Akt activation was not observed in the presence of the PP2A inhibitor okadaic acid. ACS-1 effects on PP2A activity were independent of ARE activation and cAMP formation. In addition to ACS-1, other dithiolethione compounds showed similar effects in reducing Akt activation, suggesting that this class of compounds may have other effects beyond chemoprevention.

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Related in: MedlinePlus

Scheme of protein interactions. Akt is activated by convergent pathways in human cancers. ACS-1 inhibits Akt activation by increasing the activity of PP2A and not by altering EGFR or integrin signaling.
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Figure 7: Scheme of protein interactions. Akt is activated by convergent pathways in human cancers. ACS-1 inhibits Akt activation by increasing the activity of PP2A and not by altering EGFR or integrin signaling.


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

Switzer CH, Ridnour LA, Cheng RY, Sparatore A, Del Soldato P, Moody TW, Vitek MP, Roberts DD, Wink DA - Oncogene (2009)

Scheme of protein interactions. Akt is activated by convergent pathways in human cancers. ACS-1 inhibits Akt activation by increasing the activity of PP2A and not by altering EGFR or integrin signaling.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472634&req=5

Figure 7: Scheme of protein interactions. Akt is activated by convergent pathways in human cancers. ACS-1 inhibits Akt activation by increasing the activity of PP2A and not by altering EGFR or integrin signaling.
Bottom Line: The effect of ACS-1 on Akt activation was not observed in the presence of the PP2A inhibitor okadaic acid.ACS-1 effects on PP2A activity were independent of ARE activation and cAMP formation.In addition to ACS-1, other dithiolethione compounds showed similar effects in reducing Akt activation, suggesting that this class of compounds may have other effects beyond chemoprevention.

View Article: PubMed Central - PubMed

Affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
The chemopreventative effects of dithiolethione compounds are attributed to their activation of antioxidant response elements (AREs) by reacting with the Nrf2/Keap1 protein complex. In this study, we show antiproliferative effects of the dithiolethione compound ACS-1 in human cancer cell lines (A549 and MDA-MB-231) by increasing the activity of the tumor suppressor protein phoshatase 2A (PP2A). ACS-1 inhibited epidermal growth factor (EGF)-induced cellular proliferation in a concentration- and time-dependent manner. Akt activation, as determined by serine-473 phosphorylation, was inhibited by ACS-1 in cells stimulated with either EGF or fibronectin. Furthermore, ACS-1 inhibited mammalian target of rapamycin signaling and decreased c-myc protein levels. ACS-1 did not proximally alter EGF receptor or integrin signaling, but caused a concentration-dependent increase in PP2A activity. The effect of ACS-1 on Akt activation was not observed in the presence of the PP2A inhibitor okadaic acid. ACS-1 effects on PP2A activity were independent of ARE activation and cAMP formation. In addition to ACS-1, other dithiolethione compounds showed similar effects in reducing Akt activation, suggesting that this class of compounds may have other effects beyond chemoprevention.

Show MeSH
Related in: MedlinePlus