title: Cyclooxygenase-2 positively regulates Akt signalling and enhances survival of erythroleukemia cells exposed to anticancer agents.
abstract: Cyclooxygenase-2 (COX-2) has been found to be highly expressed in many types of cancers and to contribute to tumorigenesis via the inhibition of apoptosis, increased angiogenesis and invasiveness. In hematological malignancies, COX-2 expression was found to correlate with poor patient prognosis. However, the exact role of COX-2 expression in these malignancies, and particularly in erythroleukemias, remains unclear. The aim of this work was to describe and understand the relationships between COX-2 expression and apoptosis rate in erythroleukemia cells after apoptosis induction by several anticancer agents. We used three different erythroleukemia cell lines in which COX-2 expression was modulated by transfection with either COX-2 siRNA or COX-2 cDNA. These cellular models were then treated with apoptosis inducers and apoptosis onset and intensity was followed. Cell signalling was evaluated in unstimulated transfected cells or after apoptosis induction. We found that COX-2 inhibition rendered erythroleukemia cells more sensitive to apoptosis induction and that in cells overexpressing COX-2 apoptosis induction was reduced. We demonstrated that COX-2 inhibition decreased the pro-survival Akt signalling and activated the negative regulator of Akt signalling, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Conversely, in COX-2 overexpressing cells, Akt signalling was activated and PTEN was inhibited. In these last cells, inhibition of casein kinase 2 or Akt signalling restored sensitivity to apoptotic agents. Our findings highlighted that COX-2 can positively regulate Akt signalling mostly through PTEN inhibition, partly via casein kinase 2 activation, and enhances survival of erythroleukemia cells exposed to anticancer agents.
authors: FR 3503 GEIST, EA 1069 Laboratoire de Chimie des Substances Naturelles, GDR CNRS 3049, Faculté de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France.
authors: Julian
authors: J
authors: Bertrand
authors: Bertrand
authors: B
authors: Liagre
authors: Lamia
authors: L
authors: Ghezali
authors: Jean-Louis
authors: JL
authors: Beneytout
authors: David Yannick
authors: DY
authors: Leger
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D001152:Arsenicals; D010087:Oxides; D034741:RNA, Small Interfering; D005047:Etoposide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D019311:Staurosporine; D000077237:Arsenic Trioxide; D005472:Fluorouracil