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 difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency

Ribose 5-phosphate isomerase (RPI) deficiency is an enzymopathy of the pentose phosphate pathway. It manifests with progressive leukoencephalopathy and peripheral neuropathy and belongs, with one sole diagnosed case, to the rarest human disorders. The single patient was found compound heterozygous for a RPI frameshift and a missense (RPI(Ala61Val)) allele. Here, we report that two patient-derived cell lines differ in RPI enzyme activity, enzyme concentration, and mRNA expression. Furthermore, we present a transgenic yeast model, which exhibits metabolite- and enzyme-activity changes that correspond to the human syndrome and show that the decrease in RPI activity in patient cells is not fully attributable to the residue exchange. Taken together, our results demonstrate that RPI deficiency is caused by the combination of a RPI null allele with an allele that encodes for a partially active enzyme which has, in addition, cell-type-dependent expression deficits. We speculate that a low probability for comparable traits accounts for the rareness of RPI deficiency

Estrogen receptor beta activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo

Estrogen receptor (ER)-β has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERβ coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERβ, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERβ agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERβ-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma