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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

ACS-1 effects PP2A activity independent of protein production or phase II activation. Serum starved MB231 cells were treated with ACS-1 for 2 hours. (A) Western blot analysis of HO-1 and actin indicate that ARE controlled genes are not upregulated within the time of PP2A activation by ACS-1. (B) MB231 cells were exposed to 50 μM ACS-1 for indicated times and the induction of phase II genes (UGTA1, GSTP1, GCT1, and GCLM) were measured by RT-PCR. (C) Effect of ACS-1 on cellular cAMP levels. MB231 cells were exposed to forskolin or ACS-1 for 2 hours and cAMP was measured via ELISA.
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Figure 6: ACS-1 effects PP2A activity independent of protein production or phase II activation. Serum starved MB231 cells were treated with ACS-1 for 2 hours. (A) Western blot analysis of HO-1 and actin indicate that ARE controlled genes are not upregulated within the time of PP2A activation by ACS-1. (B) MB231 cells were exposed to 50 μM ACS-1 for indicated times and the induction of phase II genes (UGTA1, GSTP1, GCT1, and GCLM) were measured by RT-PCR. (C) Effect of ACS-1 on cellular cAMP levels. MB231 cells were exposed to forskolin or ACS-1 for 2 hours and cAMP was measured via ELISA.

Mentions: Heme oxygenase-1 (HO-1), a gene product that is induced by dithiolethiones via Nrf2/ARE, is not induced within the exposure time of ACS-1 that elicited the increase in PP2A activity (Figure 6A). Additionally, the inhibition of pAkt-(ser473) by ACS-1 is not effected by the presence of the protein synthesis inhibitor G418 (data not shown). Furthermore, phase II genes are not fully activated by ACS-1 within the two hours of PP2A activation, but are subsequently activated at later time points as determined by RT-PCR of MB231 cells treated with 50 μM ACS-1 (Figure 6B). Therefore it appears that ACS-1 activates the tumor suppressor PP2A independent of de novo protein synthesis and PP2A functions to inhibit Akt signaling independently of Nrf2/ARE activation.


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)

ACS-1 effects PP2A activity independent of protein production or phase II activation. Serum starved MB231 cells were treated with ACS-1 for 2 hours. (A) Western blot analysis of HO-1 and actin indicate that ARE controlled genes are not upregulated within the time of PP2A activation by ACS-1. (B) MB231 cells were exposed to 50 μM ACS-1 for indicated times and the induction of phase II genes (UGTA1, GSTP1, GCT1, and GCLM) were measured by RT-PCR. (C) Effect of ACS-1 on cellular cAMP levels. MB231 cells were exposed to forskolin or ACS-1 for 2 hours and cAMP was measured via ELISA.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: ACS-1 effects PP2A activity independent of protein production or phase II activation. Serum starved MB231 cells were treated with ACS-1 for 2 hours. (A) Western blot analysis of HO-1 and actin indicate that ARE controlled genes are not upregulated within the time of PP2A activation by ACS-1. (B) MB231 cells were exposed to 50 μM ACS-1 for indicated times and the induction of phase II genes (UGTA1, GSTP1, GCT1, and GCLM) were measured by RT-PCR. (C) Effect of ACS-1 on cellular cAMP levels. MB231 cells were exposed to forskolin or ACS-1 for 2 hours and cAMP was measured via ELISA.
Mentions: Heme oxygenase-1 (HO-1), a gene product that is induced by dithiolethiones via Nrf2/ARE, is not induced within the exposure time of ACS-1 that elicited the increase in PP2A activity (Figure 6A). Additionally, the inhibition of pAkt-(ser473) by ACS-1 is not effected by the presence of the protein synthesis inhibitor G418 (data not shown). Furthermore, phase II genes are not fully activated by ACS-1 within the two hours of PP2A activation, but are subsequently activated at later time points as determined by RT-PCR of MB231 cells treated with 50 μM ACS-1 (Figure 6B). Therefore it appears that ACS-1 activates the tumor suppressor PP2A independent of de novo protein synthesis and PP2A functions to inhibit Akt signaling independently of Nrf2/ARE activation.

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