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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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Chemical structure of ADT and ACS-1.
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Figure 1: Chemical structure of ADT and ACS-1.

Mentions: Our previous work has suggested that the ACS-1 component, a dithiolethione with a similar structure to ADT (Figure 1), of S-NSAIDs causes a decrease in cancer cell proliferation (Moody, submitted). EGF has been shown to mediate cancer cell proliferation by activating the PI3K/Akt/mTOR pathway, which may provide therapeutic targets (Carnero et al., 2008; Dillon et al., 2007). Toward this end, we tested the potential therapeutic effect of ACS-1 on EGF-induced cell proliferation. Adherent A549 or MDA-MB-231 (MB231) cells were grown in serum-free media supplemented with EGF +/− ACS-1 and cells were counted at the indicated times. ACS-1 inhibited both A549 (Figure 2A) and MB231 (Figure 2B) proliferation in a concentration-dependent manner. In addition, ACS-1 inhibited cell proliferation in A549 (Figure 2C) and MB231 (data not shown) cells grown in media containing 10% fetal bovine serum compared to untreated controls. Cell cycle analysis of MB231 cells show that ACS-1 causes a G0/G1 block and inhibits progression into S phase as compared to serum controls (Figure 2D and Table 1), while showing no indication of dead or dying cells.


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)

Chemical structure of ADT and ACS-1.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Chemical structure of ADT and ACS-1.
Mentions: Our previous work has suggested that the ACS-1 component, a dithiolethione with a similar structure to ADT (Figure 1), of S-NSAIDs causes a decrease in cancer cell proliferation (Moody, submitted). EGF has been shown to mediate cancer cell proliferation by activating the PI3K/Akt/mTOR pathway, which may provide therapeutic targets (Carnero et al., 2008; Dillon et al., 2007). Toward this end, we tested the potential therapeutic effect of ACS-1 on EGF-induced cell proliferation. Adherent A549 or MDA-MB-231 (MB231) cells were grown in serum-free media supplemented with EGF +/− ACS-1 and cells were counted at the indicated times. ACS-1 inhibited both A549 (Figure 2A) and MB231 (Figure 2B) proliferation in a concentration-dependent manner. In addition, ACS-1 inhibited cell proliferation in A549 (Figure 2C) and MB231 (data not shown) cells grown in media containing 10% fetal bovine serum compared to untreated controls. Cell cycle analysis of MB231 cells show that ACS-1 causes a G0/G1 block and inhibits progression into S phase as compared to serum controls (Figure 2D and Table 1), while showing no indication of dead or dying cells.

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