Statins exhibit anticancer effects through modifications of the pAkt signaling pathway

  • Authors:
    • Erica Miraglia
    • Johan Högberg
    • Ulla Stenius
  • View Affiliations

  • Published online on: October 6, 2011     https://doi.org/10.3892/ijo.2011.1223
  • Pages: 867-875
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Abstract

Statins are cholesterol lowering drugs that exhibit antitumor effects in several in vitro and in vivo models, and epidemiological studies indicate that statins prevent cancer. However, the molecular mechanism underlying the effects of statins still needs to be elucidated. We previously demonstrated that single doses of different statins rapidly affect Akt signaling via the purinergic receptor P2X7. In particular, statins down-regulated nuclear pAkt. Here, we report that long-term treatment of A549 cells with high concentrations of statins (15-75 µM) selects cell sub-populations exhibiting altered P2X receptor expression, signs of increased PTEN activity, enhanced PHLPP2, decreased PI3K p110β and inhibited downstream pAkt signaling. Furthermore, the nuclear accumulation of pAkt in response to insulin was inhibited in selected cells. Statin-selected cells displayed reduced proliferation rate and were more vulnerable to etoposide- and 5-fluorouracil-elicited cytotoxic effects. The stability of a selected phenotype (50 µM) was tested for three weeks in the absence of statins. This resulted in a reversal of some, but not all alterations. Importantly, the truncated nuclear insulin response was retained. We conclude that long-term treatment with high doses of statins selects cells exhibiting stable alterations in insulin-Akt signaling and which are vulnerable to DNA damage. Our studies strengthen the hypothesis that an altered Akt signaling has a role in chemopreventive effects of statins.

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March 2012
Volume 40 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Miraglia E, Högberg J and Stenius U: Statins exhibit anticancer effects through modifications of the pAkt signaling pathway. Int J Oncol 40: 867-875, 2012.
APA
Miraglia, E., Högberg, J., & Stenius, U. (2012). Statins exhibit anticancer effects through modifications of the pAkt signaling pathway. International Journal of Oncology, 40, 867-875. https://doi.org/10.3892/ijo.2011.1223
MLA
Miraglia, E., Högberg, J., Stenius, U."Statins exhibit anticancer effects through modifications of the pAkt signaling pathway". International Journal of Oncology 40.3 (2012): 867-875.
Chicago
Miraglia, E., Högberg, J., Stenius, U."Statins exhibit anticancer effects through modifications of the pAkt signaling pathway". International Journal of Oncology 40, no. 3 (2012): 867-875. https://doi.org/10.3892/ijo.2011.1223