Modulation of PI3K/Akt pathway by E1a mediates sensitivity to cisplatin.
In order to investigate the molecular mechanisms implicated in the induction of chemo sensitivity by adenovirus E1a gene expression, we decided to investigate which signal transduction pathways could be affected by the E1a gene in Human Normal Fibroblast (IMR90). No effect was observed in SAPK pathways (p38MAPK and JNK), but E1a was able to affect the Akt activation mediated by insulin. This result was confirmed by transient transfection experiments performed in Cos-7 cells and also observed in other transformed cell lines such as A431. Furthermore, E1a expression induces a decrease in the basal status of Akt activity. Finally we demonstrated that E1a is able to block the Akt activation mediated by cisplatin and correlates with a sensitive phenotype. In summary, our data demonstrate that specific inhibition of the PI3K/Akt pathway mediates some of the biological properties of E1a such as induction of chemosensitivity.
Guinea Viniegra
Juan
J
Unidad de Patología Molecular, Clínica Puerta de Hierro, C/San Martín de Porres 4, 28035 Madrid, Spain.
Hernández Losa
Javier
J
Sánchez-Arévalo
Victor Javier
VJ
Parada Cobo
Carlos
C
Fernández Soria
Victor Manuel
VM
Ramón y Cajal
Santiago
S
Sánchez-Prieto
Ricardo
R
D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D011905:Genes, ras; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D002945:Cisplatin; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human