Linking apoptosis to cancer metabolism: Another missing piece of JuNK.

Cancer cells become dependent on aerobic glycolysis to sustain rapid proliferation and escape apoptosis. How this metabolic change, also known as the Warburg effect, is linked to apoptosis remains largely unknown. Our new data place c-Jun N-terminal kinase in the center of a hub regulating apoptosis and cancer metabolism.Foundation for Liver Research; Kay Kendall Leukemia Fun

Feeding the Hedgehog: A new meaning for JNK signalling in liver regeneration

variousBrunel University Londo

Editorial: The Warburg effect regulation under siege: The intertwined pathways in health and disease

Bloodwis

Addressing the interplay between apoptosis and glucose metabolism in liver cirrhosis and hcc

Introduction: Pro-inflammatory signalling in the liver promotes the appearance of a metabolic phenotype that involves the transition from mitochondrial respiration to aerobic glycolysis. It was demonstrated that this metabolic shift occurs during the transition from healthy and early stage of liver injury (NAFLD/NASH, ALD to late stage of disease (i.e. cirrhosis), and further escalates during HCC development.1,2This metabolic signature enables dividing cells to satisfy anabolic and energetic needs for biomass production and to suppress apoptotic signalling, which is consistent with increased compensatory hepatic cell proliferation typical of cirrhotic and HCC livers. However other studies in contrast have suggested that hepatocytes are unable to sustain glycolysis during late stage of chronic liver disease.3 Method: We used unbiased gene expression analyses of microarray datasets to investigate the expression of glycolytic genes in cirrhotic and HCC livers and correlated their expression with patient outcome. Furthermore, by using a combination of in vitro and in vivo analyses we have characterised the abilities of a novel anti-apoptotic gene to regulate aerobic glycolysis in liver cirrhosis and HCC. Results: mRNA profiling showed significantly higher expression of glycolytic transcripts in cirrhotic and HCC livers compared to normal quiescent livers (P < 0.05). Up regulation of Glut1, Hk1, Hk2, G6PI, and PFKLwas seen in HCC livers compared to their adjacent non-tumour tissues (P < 0.001). Notably, expression of enzymes regulating mitochondrial activity (Pdha, Pdk) was unchanged between non-tumour tissues and late stage of HCC. Moreover, up regulation of a novel anti-apoptotic gene positively correlated with increased expression of glycolytic transcripts in a group of cirrhotic patients prospectively classified as poor prognosis based on HCC development, and promotes the aerobic glycolysis of hepatoma cells. Conclusion: In summary, our findings delineate a putative link between aerobic glycolysis and suppression of apoptosis that is an important part of the progression of cirrhosis to HCC. The identification of the mechanism regulating this link may lead to design new therapeutic strategies for human liver disease

STARD1: a new rising StAR in cholesterol-mediated hepatocarcinogenesis

CommentaryFunding: SP and CB acknowledge the research funding from Rosetrees Trust (M894) and Guts UK (DGO2019_02)

Inhibition of mapk signalling promotes cell cycle arrest and sensitises intrahepatic cholangiocarcinoma cells to chemotherapy

Introduction: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, accounting for approximately 15% of cases of primary liver cancer. Although new treatments have increased survival for many other cancers, including the more common primary hepatocellular carcinoma, treatment strategies and survival for patients with ICC have seen little improvement. Our previous studies suggest that the mitogen-activated protein kinase (MAPK) signalling plays a central role in the regulation of cell proliferation in human ICC. However the molecular mechanisms are poorly understood. In this study, we aim to explore whether inhibition of the MAPK pathway and its downstream effectors enhances the sensitisation of ICC cells to the chemotherapeutic agent cisplatinum. Method: We used a combinatorial approach of immunohistochemical and gene expression analyses to investigate the expression of MAPK-related genes in ICC tumours. Furthermore, by using in-vitroand in-vivoanalyses we have characterised the function of a novel MAPK downstream effector in ICC cells. Results: The expression of MAPK signalling was determined by immunohistochemical staining in tumour samples from a cohort of 14 ICC patients. High expression of phospho-activated MAPK was observed in 71.4% (10/14) of ICC cases as compared with surrounding nontumour tissue. Likewise, expression of JDP, a downstream effector of the MAPK signalling, was scored as high intensity in 64.3% (9/14). Strikingly, elevated expression of JDP transcripts was also observed in two independent cohorts of human ICC (n = 149 and n = 109 per group, respectively) compared to surrounding normal liver tissue. Consistent with the in-vivo analyses of human samples, immunoblotting analyses showed constitutive activation of MAPK and expression of JDP in ICC-derived cells (i.e. SG231, CCLP-1 and HuCCT1). Using loss-of-function analyses, we demonstrates that knockdown of JDP in ICC-derived cells resulted in cell cycle arrest and reduced expression of cell cycle regulators (i.e. cyclins), and had minimal effect on apoptosis. Chemical inhibition of JDP significantly sensitises ICC-derived cells to cisplatinum (P < 0.001). Conclusion: These results demonstrate that enhanced activation of MAPK signalling is important for ICC cell proliferation and suggest that targeting its downstream effectors is a potential therapeutic strategy for ICC

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

Commodity risk assessment of grafted plants of Malus domestica from Moldova

The European Commission requested the EFSA Panel&nbsp;on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as ‘High risk plants, plant products and other objects’. This Scientific Opinion covers plant health risks posed by defoliated and in dormant phase, grafted bare rooted plants for planting of Malus domestica imported from Moldova, taking into account the available scientific information, including the technical information provided by the applicant country. A list of 1,118 pests potentially associated with the commodity species was compiled. The relevance of these pests was assessed following defined criteria and based on evidence. The EU-quarantine pest Xiphinema rivesi non-EU populations fulfilled these criteria and was selected for further evaluation. For this pest, the risk mitigation measures proposed in the technical dossier from Moldova were evaluated taking into account the possible limiting factors. For this pest, an expert judgement is given on the likelihood of pest freedom taking into consideration the risk mitigation measures acting on it, including uncertainties associated with the assessment. The Expert Knowledge Elicitation indicated, with 95% certainty, that between 9,991 and 10,000 plants per 10,000 would be free of X. rivesi