Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs.
Antitumorigenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well established in several types of cancer disease. However, the mechanisms driving these processes are not understood in all details. In our study, we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent antiproliferative 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, as assessed by analysing the cell cycle profile and expression of cell cycle regulating proteins. 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), but not GDF-15, in antiproliferative effects of indomethacin in LNCaP cells. Interestingly, we also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21(Cip1/Waf1) level and its intracellular localisation might be influenced by Akt2. Knock-down of SHIP2 by RNAi in PTEN negative prostate and colon cancer cell lines resulted in higher sensitivity to antiproliferative effects of indomethacin. Our data suggest novel mechanisms of NSAIDs antiproliferative 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. Thus, unexpectedly, multiple defects in negative regulation of the PKB/Akt pathway may contribute to increased sensitivity to chemopreventive effects of these widely used drugs.
Department of Cytokinetics, Institute of Biophysics, AS CR, Brno, Czech Republic.
Eva
E
Lincová
Ales
A
Hampl
Zuzana
Z
Pernicová
Andrea
A
Starsíchová
Pavel
P
Krcmár
Miroslav
M
Machala
Alois
A
Kozubík
Karel
K
Soucek
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases; D011471:Prostatic Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D055436:Growth Differentiation Factor 15; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D007213:Indomethacin