Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs
| Authors | |
|---|---|
| Year of publication | 2009 |
| Type | Article in Periodical |
| Magazine / Source | Biochemical Pharmacology |
| MU Faculty or unit | |
| Citation | |
| Field | Genetics and molecular biology |
| Keywords | NSAIDs; Protein kinase B/Akt; Akt2 isoform; PTEN; SHIP2; Anti proliferative effects |
| Description | The basis of antitumor effects of non-steroidal anti-inflammatory drugs (NSAIDs) is not understood yet. Here we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent anti proliferative effects of NSAIDs. The prostate cancer cell line LNCaP, lacking both critical enzymes in the negative control of PKB/Akt activation, PTEN and SHIP2, was the most sensitive to these effects. We found that p53 protein and its signalling pathway is not involved in early antiproliferative action of the selected NSAID-indomethacin. RNAi provided evidence for the involvement of p21(Cip1/Waf1). We also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our data suggest novel mechanisms of NSAIDs anti proliferative action in cancer epithelial cells, which depends on the status of negative regulation of the PKB/Akt pathway and the isoform-specific action of Akt2. |