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Aspirin Protects Caco-2 Cells from Apoptosis after Serum Deprivation through the Activation of a Phosphatidylinositol 3-Kinase/AKT/p21^Cip/WAF1Pathway

Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano", Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" del Consiglio Nazionale delle Ricerche, Università "Federico II", Napoli, Italy

Our previous studies indicated that millimolar doses of aspirin induced growth arrest and resistance to anticancer drug treatment in Caco-2 cells. The present study was designed to better elucidate at the molecular level the effect of aspirin treatment on pathways that regulate cell death during serum withdrawal. Caco-2 cells were cultured under serum deprivation in the presence or absence of aspirin. Effects on cell cycle, phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein (MAP) kinase pathways were investigated. We found that aspirin, but not the selective cyclooxygenase-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398); prevented apoptosis and G₂/M transition after prolonged Caco-2 cells serum deprivation. Aspirin-dependent inhibition of apoptosis and G₂/M transition was prevented by treatment with the PI3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), but not with the MAP kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059). The effects of aspirin were mediated at molecular levels, through activation of PI3-kinase/AKT pathway and increase in the p21^Cip/WAF1 level. The ability of aspirin to activate AKT protein was observed also in presence of etoposide cotreatment. Our data indicate a new intracellular target of aspirin with potential clinical impact for treatment schedules involving both anticancer agents and aspirin in malignancies.

Address correspondence to: Prof. Angela M. Acquaviva, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università "Federico II", via S. Pansini 5, 80131 Napoli, Italy. E-mail: angacqua{at}unina.it

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