title: Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity.
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.
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Switzer
authors.forename: L A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: R Y S
authors.initials: RY
authors.lastname: Cheng
authors.forename: A
authors.initials: A
authors.lastname: Sparatore
authors.forename: P
authors.initials: P
authors.lastname: Del Soldato
authors.forename: T W
authors.initials: TW
authors.lastname: Moody
authors.forename: M P
authors.initials: MP
authors.lastname: Vitek
authors.forename: D D
authors.initials: DD
authors.lastname: Roberts
authors.forename: D A
authors.initials: DA
authors.lastname: Wink
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016588:Anticarcinogenic Agents; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2
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