title: Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway.
abstract: Heme oxygenase-1 can play a protective role against cellular stress. In colon cancer cells, these effects would be relevant to oncogenesis and resistance to chemotherapy. The aim of the study was to examine the effects of heme oxygenase-1 induction on cell survival in a human colon cancer cell line, Caco-2. Serum deprivation induced apoptosis, reduced Akt and p38 phosphorylation, and increased p21(Cip/WAF1) levels. Heme oxygenase-1 induction by treatment with cobalt protoporphyrin IX resulted in resistance to apoptosis, activation of Akt, reduction in p21(Cip/WAF1) levels and modification of bcl2/bax ratio towards survival. Indomethacin reduced apoptosis but in contrast to heme oxygenase-1, arrested cells in G0/G1. Apoptosis was also inhibited by the heme oxygenase metabolites bilirubin and biliverdin but the CO donor tricarbonyldichlororuthenium(II) dimer did not exert significant effects. Protection against apoptosis in cells treated with cobalt protoporphyrin IX was reverted by incubation with heme oxygenase-1 small interfering RNA. This study shows an antiapoptotic effect of heme oxygenase-1 in colon cancer cells which could be mediated by the formation of bilirubin and biliverdin. Our results support an antiapoptotic role for HO-1 in these cells and provide a mechanism by which overexpression of HO-1 may promote tumor resistance to stress in conditions of limited nutrient supply. We have extended these observations by demonstrating that these effects are independent of p38 but are mediated via Akt pathway.
authors.affiliation: Department of Pharmacology, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjasot, Valencia, Spain.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
authors.forename: Javier
authors.initials: J
authors.lastname: Megías
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Terencio
authors.forename: María José
authors.initials: MJ
authors.lastname: Alcaraz
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011524:Protoporphyrins / Q000494:pharmacology
chemical_list: C493956:CDKN1A protein, human; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt