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Enzastaurin‐induced apoptosis in glioma cells is caspase‐dependent and inhibited by BCL‐X L
Author(s) -
Rieger Johannes,
Lemke Dieter,
Maurer Gabriele,
Weiler Markus,
Frank Brigitte,
Tabatabai Ghazaleh,
Weller Michael,
Wick Wolfgang
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05586.x
Subject(s) - protein kinase b , gsk 3 , apoptosis , microbiology and biotechnology , caspase , kinase , biology , phosphorylation , chemistry , cancer research , programmed cell death , biochemistry
The novel protein kinase C‐β inhibitor enzastaurin (ENZA) induced apoptosis in LNT‐229 and T98G cells whereas A172 cells were resistant. Further, ENZA reduced proliferation in glioblastoma‐initiating cells T 269 and T 323 but did not induce apoptosis. ENZA‐induced apoptosis involved cleavage of caspases 3, 8, and 9 and led to mitochondrial cytochrome c release and was strongly suppressed by the broad spectrum caspase inhibitor zVAD‐fmk but only slightly by the expression of the viral caspase 1/8 inhibitor cytokine response modifier‐A. ENZA did not reduce the phosphorylation of protein kinase B (Akt), but of p70 S6 kinase and of its substrate S6 protein in T98G cells. Inhibition of the phosphatidylinositol 3 kinase signaling pathway did not restore sensitivity of A172 cells towards ENZA, and constitutively active Akt did not protect LNT‐229 and T98G cells from ENZA‐induced apoptosis. Dephosphorylation of glycogen synthase kinase 3β, a biomarker of ENZA action, and cell death induction by ENZA were separately regulated. Inhibition or activation of Akt only weakly modulated ENZA‐induced dephosphorylation of glycogen synthase kinase 3β. In ENZA‐resistant A172 cells, apoptosis ligand 2 (Apo2L.0)‐induced cleavage of caspases 3, 8, and 9 was increased by ENZA, resulting in synergistic activity of ENZA and Apo2L.0.