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

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

Universal and Specific Functions of STAT3in Solid Tumours

STAT3 is constitutively activated in a high percentage of tumours and tumourderived cells of both liquid and solid origin, often correlating with aggressive disease and bad prognosis. Persistent STAT3 activity, to which tumours often become addicted, is mostly due to the aberrant activation of pro-oncogenic/proinflammatory signals that can trigger its phosphorylation, such as oncogenes, growth factor receptors and cytokines. Among STAT3-mediated functions are increased survival and proliferation, enhanced angiogenesis, motility and invasion, and down-modulation of anti-tumour immune responses. Moreover, STAT3 was recently shown to play unexpected roles in regulating cell metabolism and mitochondrial activity via both transcriptional and non-transcriptional mechanisms. Here, we review the main knowledge about the role of STAT3 in solid tumours, with a particular focus on breast cancer and our recent work with mouse models

Psoriasis: A STAT3-centric view

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

STAT3 in cancer: A double edged sword

The transcription factor signal transducer and activator of transcription (STAT) 3 is activated downstream of cytokines, growth factors and oncogenes to mediate their functions under both physiological and pathological conditions. In particular, aberrant/unrestrained STAT3 activity is detected in a wide variety of tumors, driving multiple pro-oncogenic functions. For that, STAT3 is widely considered as an oncogene and is the object of intense translational studies. One of the distinctive features of this factor is however, its ability to elicit different and sometimes contrasting effects under different conditions. In particular, STAT3 activities have been shown to be either pro-oncogenic or tumor-suppressive according to the tumor aetiology/mutational landscape, suggesting that the molecular bases underlining its functions are still incompletely understood. Here we discuss some of the properties that may provide the bases to explain STAT3 heterogeneous functions, and in particular how post-translational modifications contribute shaping its sub-cellular localization and activities, the cross talk between these activities and cell metabolic conditions, and finally how its functions can control the behaviour of both tumor and tumor microenvironment cell populations