STAT3: a multifaceted oncoprotein

Guanizo, Aleks C.; Fernando, C. A. N.; Garama, Daniel J.; Gough, Daniel J.

doi:10.1080/08977194.2018.1473393

Cited by 148 publications

(110 citation statements)

References 126 publications

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“…IL-6 and IL-23 induce Th17 cell differentiation through activation of the STAT3 signaling (Korn et al, 2009;Dong, 2008). Moreover, the phosphorylation of STAT3 (phospho-STAT3) at Y705 residue is known to be required for Th17 cell differentiation (Guanizo et al, 2018;Renner et al, 2008). Interestingly, the nuclear dimeric PKM2 form can act as a protein kinase and phosphorylate STAT3 at Y705 in the nucleus, enhancing its transcriptional activity and promoting tumor growth (Gao et al, 2012).…”

Section: Pkm2 Promotes Stat3 Phosphorylation In Th17 Cellsmentioning

confidence: 99%

PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

Damasceno

Prado

Veras

et al. 2020

Journal of Experimental Medicine

166

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Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell–specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell–mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.

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Section: Pkm2 Promotes Stat3 Phosphorylation In Th17 Cellsmentioning

confidence: 99%

PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

Damasceno

Prado

Veras

et al. 2020

Journal of Experimental Medicine

166

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“…We used peritoneal exudate cells (PECs) for these studies because of the known requirement for STAT3 in growth factor signalling and differentiation (e.g. CSF-1, GM-CSF pathways) 28 , moreover, PECs represent the local immunological environment, consisting predominately of myeloid cells 29 . We found that STAT3 SA PECs have a significant defect in both resting glycolysis and the early glycolytic burst observed in wild-type macrophages following LPS-challenge as determined by assaying the extracellular acidification rate (ECAR) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

STAT3 Serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

Balic

Albargy

Luu

et al. 2020

Preprint

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Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor (TLR)-4 expressed on macrophages induces a robust pro-inflammatory response which has recently been shown to be dependent on metabolic reprogramming 1, 2, 3, 4 . These innate metabolic changes have been compared to the Warburg effect (also known as aerobic glycolysis) described in tumour cells 5, 6 . However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming remain unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show both ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, the production of the central immune-metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.

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“…As an important transducer of many cytokines and growth factors, STAT proteins have 7 members (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6), and STAT3 is the most widely known and researched [28]. Compared with normal tissues, STAT3 is overexpressed or constitutively activated in about 70% of human solid tumors and in 94% of ovarian cancers [19,[29][30][31]. .…”

Section: Discussionmentioning

confidence: 99%

A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin

Zhang

Yang

Roque

et al. 2020

Preprint

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Ovarian cancer is the fifth most common cause of cancer deaths among American women. Platinum and taxane combination chemotherapy represents the first-line approach for ovarian cancer, but treatment success is often limited by chemoresistance. Therefore, it is necessary to find new drugs to sensitize ovarian cancer cells to chemotherapy. Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling plays an important role in oncogenesis. Using a novel approach called advanced multiple ligand simultaneous docking (AMLSD), we developed a novel nonpeptide small molecule, LLL12B, which targets the STAT3 pathway. In this study, LLL12B inhibited STAT3 phosphorylation (tyrosine 705) and the expression of its downstream targets, which are associated with cancer cell proliferation and survival. We showed that LLL12B also inhibits cell viability, migration, and proliferation in human ovarian cancer cells. LLL12B combined with either paclitaxel or with cisplatin demonstrated synergistic inhibitory effects relative to monotherapy in inhibiting cell viability and LLL12B-paclitaxel or LLL12B-cisplatin combination exhibited greater inhibitory effects than cisplatin-paclitaxel combination in ovarian cancer cells. Furthermore, LLL12B-paclitaxel or LLL12B-cisplatin combination showed more significant in inhibiting cell migration and growth than monotherapy in ovarian cancer cells. In summary, our results support the novel small molecule LLL12B as a potent STAT3 inhibitor in human ovarian cancer cellsand suggest that LLL12B in combination with the current front-line chemotherapeutic drugs cisplatin and paclitaxel may represent a promising approach for ovarian cancer therapy.

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STAT3: a multifaceted oncoprotein

Cited by 148 publications

References 126 publications

PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

STAT3 Serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression

A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin

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