دورية أكاديمية
Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs
| العنوان: | Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs |
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| المؤلفون: | Lincová, Eva, Hampl, Aleš, Pernicová, Zuzana, Staršíchová, Andrea, Krčmář, Pavel, Machala, Miroslav, Kozubík, Alois, Souček, Karel |
| المصدر: | ISSN: 0006-2952. |
| بيانات النشر: | HAL CCSD Elsevier |
| سنة النشر: | 2009 |
| المجموعة: | Archive ouverte HAL (Hyper Article en Ligne, CCSD - Centre pour la Communication Scientifique Directe) |
| مصطلحات موضوعية: | Cdk2, COX-1, COX-2, Egr-1, ERK, GAPDH, GDF-15, JNK, MAPK, NSAIDs, PDK1, PGE, PI3K, PIP3, PKB, POLR2A, PTEN, SHIP, Protein kinase B/Akt, Akt2 isoform, SHIP2, Antiproliferative effects |
| الوصف: | International audience ; 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 involvement of p21, 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 and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | hal-00506792; https://hal.archives-ouvertes.fr/hal-00506792Test; https://hal.archives-ouvertes.fr/hal-00506792/documentTest; https://hal.archives-ouvertes.fr/hal-00506792/file/PEER_stage2_10.1016%252Fj.bcp.2009.05.001.pdfTest |
| DOI: | 10.1016/j.bcp.2009.05.001 |
| الإتاحة: | https://doi.org/10.1016/j.bcp.2009.05.001Test https://hal.archives-ouvertes.fr/hal-00506792Test https://hal.archives-ouvertes.fr/hal-00506792/documentTest https://hal.archives-ouvertes.fr/hal-00506792/file/PEER_stage2_10.1016%252Fj.bcp.2009.05.001.pdfTest |
| حقوق: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.7F39A95C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.bcp.2009.05.001 |
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