Acquired activation of the Akt/cyclooxygenase-2/Mcl-1 pathway renders lung cancer cells resistant to apoptosis.

Molecular Pharmacology
Wenjie ChenYong Lin

Abstract

Acquired apoptosis resistance plays an important role in acquired chemoresistance in cancer cells during chemotherapy. Our previous observations demonstrated that acquired tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells was associated with Akt-mediated stabilization of cellular FLICE-like inhibitory protein (c-FLIP) and Mcl-1. In this report, we determined that these cells also have acquired resistance to apoptosis induced by chemotherapeutics such as cisplatin and doxorubicin (Adriamycin), which was detected in vitro in cell cultures and in vivo in xenografted tumors. We further found that cyclooxygenase-2 (COX-2) is dramatically overexpressed in cells with acquired apoptosis resistance. COX-2 seems to be a crucial mediator in acquired apoptosis resistance because suppressing COX-2 activity with a chemical inhibitor or reducing COX-2 protein expression level with COX-2 small interfering RNA dramatically alleviated resistance to therapeutic-induced apoptosis. Inhibiting Akt markedly suppressed COX-2 expression, suggesting COX-2 is a downstream effector of this cell survival kinase-mediated apoptosis resistance. Furthermore, the expression of Mcl-1 but not c-FLIP was significantly reduced ...Continue Reading

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Citations

Jul 4, 2012·Journal of Natural Medicines·Chatchai ChaothamPithi Chanvorachote
May 15, 2012·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Cheng-lin YangGui-xing Jiang
Aug 31, 2014·Pharmacology & Therapeutics·Johannes Belmar, Stephen W Fesik
Jul 3, 2013·BioFactors·Eftychia Oikonomou, Alexander Pintzas
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Sep 19, 2014·Journal of Veterinary Internal Medicine·M CamposJ A Mol
Oct 21, 2018·Journal of Cellular Physiology·Nasser Hashemi GoradelKeywan Mortezaee
Jun 30, 2019·Biomolecules·Nand Kishor RoyAjaikumar B Kunnumakkara
Feb 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Wanatchaporn ArunmaneeChatchai Chaotham

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