PMID- 19861406 OWN - NLM STAT- MEDLINE DCOM- 20100304 LR - 20211020 IS - 1557-3125 (Electronic) IS - 1541-7786 (Print) IS - 1541-7786 (Linking) VI - 7 IP - 11 DP - 2009 Nov TI - Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function. PG - 1871-81 LID - 10.1158/1541-7786.MCR-09-0194 [doi] AB - Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and significant technical advances in surgical and radiation treatment, the impact on clinical outcome for patients with malignant gliomas is disappointing. We have previously shown that tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell survival via binding to the Fn14 receptor, activation of the NF-kappaB pathway, and upregulation of BCL-X(L) gene expression. Here, we show that TWEAK treatment of glioma cells leads to phosphorylation of Akt and BAD. TWEAK stimulation results in the phosphorylation of both Akt1 and Akt2. However, small interfering RNA (siRNA)-mediated depletion of either Akt1 or Akt2 showed that BAD serine 136 phosphorylation is dependent specifically on Akt2 function. Depletion of Akt2 expression by siRNA also abrogates TWEAK-stimulated glioma cell survival, whereas no effect on glioma cell survival was observed after siRNA-mediated depletion of Akt1 expression. Surprisingly, although siRNA-mediated depletion of BAD in glioma cells abrogates cytotoxic- and chemotherapy-induced apoptosis, TWEAK still displays a strong protective effect, suggesting that BAD serine 136 phosphorylation plays a minor role in TWEAK-Akt2-induced glioma cell survival. We also report here that AKT2 gene expression levels increased with glioma grade and inversely correlate with patient survival. Additionally, immunohistochemical analysis showed that Akt2 expression positively correlates with Fn14 expression in glioblastoma multiforme specimens. We hypothesize that the TWEAK-Fn14 signaling axis functions, in part, to enhance glioblastoma cell survival by activation of the Akt2 serine/threonine protein kinase. FAU - Fortin, Shannon P AU - Fortin SP AD - Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA. FAU - Ennis, Matthew J AU - Ennis MJ FAU - Savitch, Benjamin A AU - Savitch BA FAU - Carpentieri, David AU - Carpentieri D FAU - McDonough, Wendy S AU - McDonough WS FAU - Winkles, Jeffrey A AU - Winkles JA FAU - Loftus, Joseph C AU - Loftus JC FAU - Kingsley, Christopher AU - Kingsley C FAU - Hostetter, Galen AU - Hostetter G FAU - Tran, Nhan L AU - Tran NL LA - eng GR - R01 CA130940/CA/NCI NIH HHS/United States GR - R01 NS55126/NS/NINDS NIH HHS/United States GR - R01 CA130940-01/CA/NCI NIH HHS/United States GR - R01 NS055126/NS/NINDS NIH HHS/United States GR - R01 CA103956/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20091027 PL - United States TA - Mol Cancer Res JT - Molecular cancer research : MCR JID - 101150042 RN - 0 (BAD protein, human) RN - 0 (Cytokine TWEAK) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (TNFRSF12A protein, human) RN - 0 (TNFSF12 protein, human) RN - 0 (TWEAK Receptor) RN - 0 (Tumor Necrosis Factors) RN - 0 (bcl-Associated Death Protein) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (AKT2 protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Apoptosis/drug effects/physiology MH - Brain Neoplasms/drug therapy/genetics/*metabolism/*pathology MH - Cell Line, Tumor MH - Cell Survival/drug effects/genetics MH - Cytokine TWEAK MH - Gene Expression Profiling MH - Glioblastoma/drug therapy/genetics/metabolism/pathology MH - Glioma/drug therapy/genetics/*metabolism/*pathology MH - Humans MH - Immunohistochemistry MH - Phosphorylation MH - Proto-Oncogene Proteins c-akt/*metabolism MH - RNA, Small Interfering/administration & dosage/genetics MH - Receptors, Tumor Necrosis Factor/metabolism MH - TWEAK Receptor MH - Transfection MH - Tumor Necrosis Factors/metabolism/*pharmacology MH - bcl-Associated Death Protein/deficiency/genetics PMC - PMC2783270 MID - NIHMS150777 EDAT- 2009/10/29 06:00 MHDA- 2010/03/05 06:00 PMCR- 2010/11/01 CRDT- 2009/10/29 06:00 PHST- 2009/10/29 06:00 [entrez] PHST- 2009/10/29 06:00 [pubmed] PHST- 2010/03/05 06:00 [medline] PHST- 2010/11/01 00:00 [pmc-release] AID - 1541-7786.MCR-09-0194 [pii] AID - 10.1158/1541-7786.MCR-09-0194 [doi] PST - ppublish SO - Mol Cancer Res. 2009 Nov;7(11):1871-81. doi: 10.1158/1541-7786.MCR-09-0194. Epub 2009 Oct 27.