474 research outputs found

    PKM2, STAT3 and HIF-1α

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    STAT3-mediated metabolic reprograming in cellular transformation and implications for drug resistance

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    Signal Transducer and Activator of Transcription (STAT)3 mediates the signaling downstream of cytokine and growth factor receptors, regulating the expression of target genes. It is constitutively phosphorylated on tyrosine (Y-P) in many tumours, where its transcriptional activity can induce a metabolic switch towards aerobic glycolysis and down-regulate mitochondrial activity, a prominent metabolic feature of most cancer cells, correlating with reduced production of ROS, delayed senescence and protection from apoptosis. STAT3 can however also localize to mitochondria, where its serine-phosphorylated (S-P) form preserves mitochondrial oxidative phosphorylation and controls the opening of the mitochondrial permeability transition pore, also promoting survival and resistance to apoptosis in response to specific signals/oncogenes such as RAS. Thus, downstream of different signals, both nuclear, Y-P STAT3 and mitochondrial, S-P STAT3 can act by promoting cell survival and reducing ROS production.Here, we discuss these properties in the light of potential connections between STAT3-driven alterations of mitochondrial metabolism and the development of drug resistance in cancer patients

    Psoriasis: A STAT3-centric view

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    Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options. Due to the oral/topical administration modality of these small molecule drugs, their lower cost, and the reduced risk of eliciting adverse immune responses, these compounds are being actively scrutinized in clinical settings. Here, we summarize the main pathological features of psoriatic conditions that provide the rationale for targeting the JAK/STAT3 axis in disease treatment
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