Journal
ONCOGENE
Volume 28, Issue 43, Pages 3837-3846Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.244
Keywords
dithiolethione; PP2A; Akt; cancer; breast; lung
Funding
- Intramural NIH HHS [Z01 BC010899-01] Funding Source: Medline
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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 anti-proliferative effects of the dithiolethione compound ACS1 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. Oncogene (2009) 28, 3837-3846; doi:10.1038/onc.2009.244; published online 24 August 2009
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