Phosphoinositide 3-Kinase/AKT1 Pathway and Human Ovarian Cancer

Abstract

SUPPLEMENTARY NOTESReport contains color Extensive studies have demonstrated that the Akt pathway is essential for cell survival and anti-apoptosis; however, alterations of Akt in human malignancy have not been documented. We have recently demonstrated significantly increased AKT1 and AKT2 kinase activity in primary ovarian carcinomas. We have also shown that PI3K is frequently activated in the specimens with activation of Akt. The majority of cases with PI3K/Akt activation are late stage and high grade. The biological significance of AKT 1 activation in human cancer was demonstrated by malignant transformation of NIH 3T3 cells transfected with constitutively active AKT1, but not cells transfected with wild type AKT1. Moreover, inhibition of PI3K/Akt pathway inhibits cell growth and induces apoptosis in human ovarian cancer cell lines. We have also observed that estrogen receptor (ER)cc interacts and activates PI3K/Akt pathway. PI3K/Akt feedback regulates ERa by phosphorylation of serine-167 of ERa. These data indicate that AKT1 kinase, which is frequently activated in human cancer, is a determinant in oncogenesis and a potential target for cancer intervention. Appendices 6 SUBJECT TERMS INTRODUCTION:The purpose of this project is to: 1) Determine the incidence and clinical significance of PI3K/AKT1 alterations in ovarian cancer; 2) Determine the role of overexpression of active and wild type PI3K and AKT1 in ovarian surface epithelial cell transformation and 3) Determine PI3K and AKT1 as targets for ovarian cancer intervention BODY:During the current budget year, we focused our efforts on the examination of incidence and clinical significance of PI3K/AKT1 alterations in human ovarian cancer and PI3K/AKT1 as a potential target for ovarian cancer intervention. I. PI3K/AKT1 is frequently activated in human primary ovarian cancer.Extensive studies have demonstrated that the Akt pathway is essential for cell survival and antiapoptosis (1); however, alterations of Akt in human malignancy have not been documented. Total 91 ovarian tumor specimens have been examined for protein expression and kinase activity of AKT 1. Activation of PI3K and AKT1 was observed in 39.3% tumor examined, however, elevated AKT1 protein level was only detected in 8.3% (2, see Appendix). We have also looked at PTEN, a tumor suppressor gene encoding dual phosphatase that dephosphorylates PI3K products (PI3,4,5P3) and inhibits AKT1 activity (3), alterations in this series of tumors. Three cases showed PTEN downregulation. These data suggest that PI3K activation is primary reason to result in elevated AKT1 kinase levels in human ovarian cancer. The majority of the tumors with PI3K/AKT1 activation are late stages and high grades indicating that alterations of PI3K/AKT1 are associated with tumor progression rather than initiation. II. Expression of constitutively activated AKT1 results in malignant phenotype in NIH 3T3cells.It has been demonstrated that wild type AKT1 was unable to transform NIH 3T3 cells (4). To determine whether activation of AK...