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.