PARP14 promotes the warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo, we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism

The ERK and JNK pathways in the regulation of metabolic reprogramming.

Most tumor cells reprogram their glucose metabolism as a result of mutations in oncogenes and tumor suppressors, leading to the constitutive activation of signaling pathways involved in cell growth. This metabolic reprogramming, known as aerobic glycolysis or the Warburg effect, allows tumor cells to sustain their fast proliferation and evade apoptosis. Interfering with oncogenic signaling pathways that regulate the Warburg effect in cancer cells has therefore become an attractive anticancer strategy. However, evidence for the occurrence of the Warburg effect in physiological processes has also been documented. As such, close consideration of which signaling pathways are beneficial targets and the effect of their inhibition on physiological processes are essential. The MAPK/ERK and MAPK/JNK pathways, crucial for normal cellular responses to extracellular stimuli, have recently emerged as key regulators of the Warburg effect during tumorigenesis and normal cellular functions. In this review, we summarize our current understanding of the roles of the ERK and JNK pathways in controlling the Warburg effect in cancer and discuss their implication in controlling this metabolic reprogramming in physiological processes and opportunities for targeting their downstream effectors for therapeutic purposes.Brunel Research Initiative & Enterprise Fund, Brunel University of London (to CB), Kay Kendall Leukemia Fund (KKL443) (to CB), 250 Great Minds Fellowship, University of Leeds (to SP), AMMF Cholangiocarcinoma Charity (to SP and PMC), and Bloodwise (17014) (to SP and CB)

An Arnoldi reduction strategy applied to the semi-analytical finite element method to model railway track vibrations

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An Arnoldi reduction applied to wave propagation model to compute railway track vibrations

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An Arnoldi reduction applied to wave propagation to model railway track vibrations

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Metacognition Mediates the Relationship Between Maladaptive Personality Traits and Levels of Personality Functioning: A General Investigation on a Nonclinical Sample

The impaired ability to reflect on one's own state of mind and that of others (called metacognition or mentalization) is a central feature of personality disorders (PDs). Metacognition involves different specific abilities, which can be selectively impaired with different PDs and personality maladaptive traits. Moreover, research in the field of PDs has indicated that personality features and metacognitive abilities are associated with the severity of personality pathologies. In this study, we tested a mediation model of the interactions between these variables on predicting levels of personality functioning in a sample of adults taken from the general population (N = 775). Results showed that the relationship between personality traits and personality functioning is partially mediated by metacognitive abilities. These findings support the hypothesis that metacognition plays a significant role in predicting the levels of impairment in personality functioning. These findings have several clinical implications

A mid-frequency method to model coupled vibro-acoustic response of a railway track

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