Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13Rα2

Rahaman, Shaik O.; Vogelbaum, Michael A.; Haque, S. Jaharul

doi:10.1158/0008-5472.can-04-3592

Cited by 106 publications

(86 citation statements)

References 50 publications

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“…Thus, it appears that no matter how it is activated, Stat3 is an essential player in keeping the apoptosis machinery at bay in GBM cells, and possibly does so by maintaining the expression of the prosurvival proteins Mcl-1 in U87 cells and Mcl-1, Bcl-2 and Bcl-X L in U251 cells (Rahaman et al, 2002). More recently, we show by chromatin immunoprecipitation employing anti-Stat3 antibody that activated Stat3 remains bound to the promoters of these prosurvival genes in GBM cells (Rahaman et al, 2005). PI3K-AKT pathway also upregulates the expression of mcl-1 and bcl-2 genes (Ballif and Blenis, 2001), suggesting that both Stat3 and PI3K-AKT target the same prosurvival genes.…”

Section: Discussionmentioning

confidence: 78%

PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells

et al. 2005

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Glioblastoma multiforme (GBM) cells frequently harbor amplification and/or gain-of-function mutation of the EGFR gene leading to the activation of multiple signaling pathways. Blockade of EGFR activation inhibited the activation of both AKT and Stat3 in U87 and D54 GBM cells and induced spontaneous apoptosis, which were associated with reduction in the steady-state level of Mcl-1. Surprisingly, inhibition of PI3 kinase (PI3K) activity, which in turn inhibited AKT activation, significantly increased the DNA-binding activity of Stat3 in U87 and D54 cells. This was not due to an increase in the level of tyrosine-phosphorylated Stat3. Conversely, ectopic expression of constitutively activated AKT significantly decreased the DNA-binding activity of Stat3 in 293T cells. Interestingly, blockade of protein phosphatase 2A activity in GBM or 293T cells by calyculin A, which activated AKT, stabilized the phosphorylation of multiple Ser/Thr residues that were located in the transactivation domain (TAD) of Stat3 and this in turn completely ablated the DNA-binding activity of Stat3. Collectively, these results suggest that both Stat3 and AKT provide survival signals in U87 and D54 cells, and Ser/Thr phosphorylation of Stat3-TAD by the PI3K-AKT pathway negatively controls the DNA-binding function of Stat3.

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Section: Discussionmentioning

confidence: 78%

PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells

et al. 2005

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“…STAT3 appears to be constitutively activated in diverse tumor-infiltrating immune cells, and ablation of STAT3 in hemopoietic cells triggers an intrinsic immune surveillance system that inhibits tumor growth and metastasis via enhanced function of DCs, T cells, NK cells, and neutrophils in tumor-bearing mice with STAT3 Ϫ/Ϫ hemopoietic cells (22). Activation of STAT3 in human glioma has been well documented (18,19,(23)(24)(25). Gliomas produce high levels of IL-10 (reviewed in Ref.…”

Section: Inhibition Of Stat3 Promotes the Efficacy Of Adoptive Transfmentioning

confidence: 99%

Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma

Fujita

Zhu

Sasaki

et al. 2008

The Journal of Immunology

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A variety of cancers, including malignant gliomas, show aberrant activation of STAT3, which plays a pivotal role in negative regulation of antitumor immunity. We hypothesized that inhibition of STAT3 signals would improve the efficacy of T cell adoptive transfer therapy by reversal of STAT3-induced immunosuppression in a murine GL261 intracranial glioma model. In vitro treatment of GL261 cells with JSI-124, a STAT3 inhibitor, reversed highly phosphorylated status of STAT3. Systemic i.p. administration of JSI-124 in glioma-bearing immunocompetent mice, but not athymic mice, resulted in prolonged survival, suggesting a role of adaptive immunity in the antitumor effect. Furthermore, JSI-124 promoted maturation of tumor-infiltrating CD11c+ dendritic cells and activation of tumor-conditioned cytotoxic T cells, enhanced dendritic cells and GL261 production of CXCL-10, a critical chemokine for attraction of Tc1 cells. When i.p. JSI-124 administration was combined with i.v. transfer of Pmel-I mouse-derived type-1 CTLs (Tc1), glioma-bearing mice exhibited prolonged survival compared with i.p. JSI-124 or i.v. Tc1 therapy alone. Flow cytometric analyses of brain infiltrating lymphocytes revealed that JSI-124-treatment enhanced the tumor-homing of i.v. transferred Tc1 cells in a CXCL-10-dependent fashion. Systemic JSI-124 administration also up-regulated serum IL-15 levels, and promoted the persistence of transferred Tc1 in the host. These data suggest that systemic inhibition of STAT3 signaling can reverse the suppressive immunological environment of intracranial tumor bearing mice both systemically and locally, thereby promoting the efficacy of adoptive transfer therapy with Tc1.

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“…The signal transducer and activator of transcription 3 is widely expressed in normal cells but its transient activation is strictly regulated by protein inhibitors of STATs (PIAS), SH2-containing tyrosine phosphatases (SHP1 and SHP2), and suppressor of cytokine signalling/extracellular signalregulated kinase (SOCS/ERK). In several human cancers including glioblastoma, a dysregulation of the above mechanisms leads to constitutive activation of STAT3 (Rahaman et al, 2005). Constitutive STAT3 activation has been linked to cancer initiation, proliferation, promotion of angiogenesis and inhibition of apoptosis.…”

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confidence: 99%

LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model

Sobo

et al. 2009

Br J Cancer

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Persistent activation of the signal transducer and activator of transcription 3 (STAT3) signalling has been linked to oncogenesis and the development of chemotherapy resistance in glioblastoma and other cancers. Inhibition of the STAT3 pathway thus represents an attractive therapeutic approach for cancer. In this study, we investigated the inhibitory effects of a small molecule compound known as LLL-3, which is a structural analogue of the earlier reported STAT3 inhibitor, STA-21, on the cell viability of human glioblastoma cells, U87, U373, and U251 expressing constitutively activated STAT3. We also investigated the inhibitory effects of LLL-3 on U87 glioblastoma cell growth in a mouse tumour model as well as the impact it had on the survival time of the treated mice. We observed that LLL-3 inhibited STAT3-dependent transcriptional and DNA binding activities. LLL-3 also inhibited viability of U87, U373, and U251 glioblastoma cells as well as induced apoptosis of these glioblastoma cell lines as evidenced by increased poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavages. Furthermore, the U87 glioblastoma tumour-bearing mice treated with LLL-3 exhibited prolonged survival relative to vehicle-treated mice (28.5 vs 16 days) and had smaller intracranial tumours and no evidence of contralateral invasion. These results suggest that LLL-3 may be a potential therapeutic agent in the treatment of glioblastoma with constitutive STAT3 activation.

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Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13Rα2

Cited by 106 publications

References 50 publications

PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells

PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells

Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma

LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model

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