<scp>STAT3</scp> Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma

Ouédraogo, Zangbéwendé Guy; Müller-Barthélémy, Mélanie; Kémény, Jean-Louis; Dedieu, V.; Biau, J.; Khalil, T.; Raoelfils, Lala Ines; Granzotto, Adeline; Pereira, Bruno; Beaudoin, Claude; Guissou, Innocent Pierre; Berger, Marc; Morel, Laurence; Chautard, Emmanuel; Verrelle, Pierre

doi:10.1111/bpa.12254

Cited by 27 publications

(26 citation statements)

References 63 publications

(98 reference statements)

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“…Moreover, this study of Lin et al evidenced a statistically significant association of pSTAT3-S727 and pSTAT3-Y705 [152]. In a cohort of 30 GBM clinical specimens and a panel of 15 GBM cell lines, we showed that pSTAT3-S727 is present in all studied human malignant glioma cell lines and all the examined GBM specimens [153]. However, pSTAT3-Y705 was not detected in some GBM cell lines or specimens and was moreover restricted to a variable number of GBM cells in the positive clinical samples.…”

Section: Constitutive Phosphorylation Of Stat3-s727supporting

confidence: 67%

“…Moreover, increased expression of the both makes worse the clinical outcome [152]. Since, pSTAT3-Y705 is not detected is some glioma specimens and does not accumulate in all glioma neoplastic cells [153], we speculate that it is not a major driver of GBM aggressiveness. In contrast, pSTAT3-S727 detected is all neoplastic cells of all GBM specimens may be a best prognostic marker, provided that a discriminative detection assay is performed.…”

Section: Stat3 and Prognosismentioning

confidence: 88%

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Role of STAT3 in Genesis and Progression of Human Malignant Gliomas

et al. 2016

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Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in glioblastoma and has been identified as a relevant therapeutic target in this disease and many other human cancers. After two decades of intensive research, there is not yet any approved STAT3-based glioma therapy. In addition to the canonical activation by tyrosine 705 phosphorylation, concordant reports described a potential therapeutic relevance of other post-translational modifications including mainly serine 727 phosphorylation. Such reports reinforce the need to refine the strategy of targeting STAT3 in each concerned disease. This review focuses on the role of serine 727 and tyrosine 705 phosphorylation of STAT3 in glioma. It explores their contribution to glial cell transformation and to the mechanisms that make glioma escape to both immune control and standard treatment.

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Section: Constitutive Phosphorylation Of Stat3-s727supporting

confidence: 67%

Section: Stat3 and Prognosismentioning

confidence: 88%

Role of STAT3 in Genesis and Progression of Human Malignant Gliomas

et al. 2016

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“…It seems that preexisting STAT3 activity in MDSCs, can skew TLR9 signaling toward supporting tumor angiogenesis while blocking antitumor immunity [48][49][50] Recently, TLR9 stimulation by CpG-ODN has been shown to activate NF-kB pathway, leading to Th1 immunostimulation and antitumor immune responses [51,52]. A promising targeted combined therapy should associate T-cell therapy and STAT3 inhibitors linked to CpG/TLR9 that could silence STAT3 in cancer cells and stromal /immune cells and favor down-regulation of cancer stem cells and antitumor immune responses [53,54].…”

Section: Discussionmentioning

confidence: 99%

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Meseure

Vacher

Alsibai

et al. 2016

Cancer Microenvironment

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Toll-like receptors (TLRs) are pattern recognition receptors mainly expressed by cells of the immune system but also by epithelial tumor cells. Little is known about expression patterns of TLR genes in breast tumors, and their clinical significance is unclear. The aim of our study was to investigate expression of TLRs pathway components in pre-invasive breast lesions and invasive breast carcinomas (IBCs). We used RT-PCR assays to quantify mRNA levels of the 10 TLR genes and genes involved in TLR pathways in 350 breast tumors from patients with known clinical/pathological status and long-term outcome. Sets of 158 breast samples were also analyzed by immunochemistry including; 40 early noninvasive breast lesions, 38 IBCs and 80 triple negative carcinomas subtype (TNCs). We identified TLR9 as the major TLR gene family member upregulated in breast tumors and more particularly in TNCs. Immunohistochemical studies demonstrated that TLR9 protein was expressed in tumor epithelial and stromal cells of the TLR9 mRNA-overexpressing tumors. TLR9 overexpression appears very early during breast carcinogenesis. High TLR9 levels were associated with favorable outcome in the TNC sub-group. TLR9 overexpression was associated with alterations of down-stream components of the TLR9 signaling pathway, epithelio-mesenchymal transition (EMT) induction and EGFR pathway deregulation. TNCs with TLR9 overexpression were significantly correlated with development of a fibrous and inflammatory microenvironment with variable status of nuclear phosphoSTAT3. Our results suggest that TLR9 could play a role in TNC carcinogenesis and could be useful as predictive biomarker and therapeutic target.Keywords Toll-like receptor 9 . Breast cancer subtypes .

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“…In case of glioblastoma (GBM) high levels of pS727 STAT3 leads to shorter progress free survival [73]. Increased level of pS727 STAT3 in GMB cell lines correlates with the increased intrinsic radioresistance nature and treatment with Gö6976 inhibitor induces radiosensitization in those GBM cell lines that had high levels of pS727 STAT3 and no or weak expression of pY705 STAT3 [74]. The differential role of pS727 and pY705 STAT3 is also seen in deciding the fate of mouse embryonic stem cells (mESC).…”

Section: Ps727 Phosphorylation and K685 Acetylation Of Stat3: The Nonmentioning

confidence: 99%

Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

Dimri¹,

Sukanya²,

De³

2017

Integr Mol Med

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STAT3 is an essential cellular transcription factor that activates a cascade of survival and proliferation signaling program in cells upon cytokine and growth factor stimulus. STAT3 forms a converging point for many upstream activated signaling pathways required for maintaining normal and oncogenic condition. As an active transcription factor, it controls transcription of downstream genes involved in various steps of cancer progression like cell proliferation, migration, immune evasion and angiogenesis. It is known to be constitutively active in many cancers with approximately 40% of breast cancer cases positive for activated STAT3. Apart from the wellstudied pY705 activation (canonical pathway), STAT3 is reported to undergo alternative post-translational modifications like pS727 and K685Ac (non-canonical pathway) that are now appearing to be responsible for triggering activated STAT3 in many cancers including breast cancer. Hence, correct designation and targeting ability of these post-translational modifications (PTM) of STAT3 signaling in any particular cancer may hold the key in treating patients with STAT3 overexpression.

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STAT3 Serine 727 Phosphorylation: A Relevant Target to Radiosensitize Human Glioblastoma

Abstract: International audienc

Cited by 27 publications

References 63 publications

Role of STAT3 in Genesis and Progression of Human Malignant Gliomas

Role of STAT3 in Genesis and Progression of Human Malignant Gliomas

Biopathological Significance of TLR9 Expression in Cancer Cells and Tumor Microenvironment Across Invasive Breast Carcinomas Subtypes

Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

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