Aspirin protects Caco-2 cells from apoptosis after serum deprivation through the activation of a phosphatidylinositol 3-kinase/AKT/p21Cip/WAF1pathway

Mol Pharmacol. 2003 Aug;64(2):407-14. doi: 10.1124/mol.64.2.407.

Abstract

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 p21Cip/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Apoptosis
  • Aspirin / pharmacology*
  • Caco-2 Cells
  • Cell Cycle / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Culture Media, Serum-Free
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / drug effects
  • Cyclins / metabolism*
  • Enzyme Activation / drug effects
  • Humans
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • CDKN1A protein, human
  • Culture Media, Serum-Free
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases
  • Aspirin