Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells

• Published in: Oncogene Vol. 21; no. 55; pp. 8404 - 8413
• Main Authors: SHAIK OHIDAR RAHAMAN, HARBOR, Phyllis C, CHERNOVA, Olga, BARNETT, Gene H, VOGELBAUM, Michael A, JAHARUL HAQUE, S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 05-12-2002; Nature Publishing Group
• Subjects: Acute-Phase Proteins - antagonists & inhibitors; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - physiology; Astrocytes; Autocrine signalling; Bcl-2 protein; Bcl-x protein; Biological and medical sciences; Brain cancer; Brain Neoplasms - pathology; Cancer therapies; Cell cycle; Cell Division - drug effects; Cell Division - physiology; Cell physiology; Cell proliferation; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Central nervous system; Cytokines; DNA binding proteins; DNA-Binding Proteins - antagonists & inhibitors; Enzyme inhibitors; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Genes; Glioblastoma; Glioblastoma - pathology; Glioblastoma multiforme; Growth factors; Humans; Interleukin 6; Janus kinase; Kinases; Mcl-1 protein; Molecular and cellular biology; Mutation; Pathogenesis; Physiological aspects; Proteins; Ribose; Risk factors; Signal transduction; Stat3 protein; STAT3 Transcription Factor; Substantia alba; Trans-Activators - antagonists & inhibitors; Transcription factors; Transcription, Genetic - drug effects; Tumor Cells, Cultured; Tumors; Tyrphostins - pharmacology; United States; United States > US; Ohio; Human; Cell proliferation; Nervous system diseases; Malignant tumor; Gene expression; Glioblastoma multiforme; IL-6; Malignant glioma; Signal transduction; Cell line; glioblastoma; Central nervous system disease; Transcription factor STAT3; Stat3; Jak-Stat signal transduction; Onc gene; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206047

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.