Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells.
Glioblastoma multiforme (GBM), the most common and malignant central nervous system tumor in humans, is highly proliferative and resistant to apoptosis. Stat3, a latent transcription factor being activated by aberrant cytokine or growth factor signaling, acts as a suppressor of apoptosis in a number of cancer cells. Here we report that GBM tumors and cell lines contain high levels of constitutively activated Stat3 when compared with normal human astrocytes, white matter, and normal tissue adjacent to tumor. The persistent activation of Stat3 is in part, attributable to an autocrine action of interleukin-6 in the GBM cell line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1 proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose) polymerase cleavage and Annexin-V staining. Expression of a dominant negative mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation of U251 cells by inhibiting the constitutive activation of Stat3. These results provide evidence that constitutive activation of Stat3 contributes to the pathogenesis of glioblastoma by promoting both proliferation and survival of GBM cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic intervention for GBM.
Rahaman
Shaik Ohidar
SO
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio, OH 44195, USA.
Harbor
Phyllis C
PC
Chernova
Olga
O
Barnett
Gene H
GH
Vogelbaum
Michael A
MA
Haque
S Jaharul
SJ
D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001932:Brain Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
D000209:Acute-Phase Proteins; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide