Imperial College London

Dr Salvatore Papa

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Research Fellow
 
 
 
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Contact

 

+44 (0)20 3313 8282s.papa

 
 
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Location

 

10N.13Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

62 results found

Bubici C, Lepore A, Papa S, 2019, ASKing no more: the emerging role of DUSP12 in the regulation of hepatic lipid metabolism, Hepatology, ISSN: 0270-9139

Accumulation of fat in liver cells not due to alcohol abuse is the hallmark of non-alcoholic fatty liver disease (NAFLD), a common condition that may progress to non-alcoholic steatohepatitis (NASH) characterized by liver inflammation.(1) Over a long period of time, NASH may lead to fibrosis with consequent cirrhosis, which in turn predisposes patients to hepatocellular carcinoma.

Journal article

Bubici C, Papa S, 2019, Editorial: The warburg effect regulation under siege: the intertwined pathways in health and disease, Frontiers in Cell and Developmental Biology, Vol: 7, ISSN: 2296-634X

Journal article

Papa S, Choy PM, Bubici C, 2019, The ERK and JNK pathways in the regulation of metabolic reprogramming, Oncogene, Vol: 38, Pages: 2223-2240, ISSN: 0950-9232

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.

Journal article

Papa S, Lee NC, Bubici C, 2018, Deciphering preventive and prognostic biomarkers of liver cancer, NCRI Cancer Conference 2018, Publisher: National Cancer Research Institute

Conference paper

Lee NCW, Carella MA, Papa S, Bubici Cet al., 2018, High expression of glycolytic genes in cirrhosis correlates with the risk of developing liver cancer, Frontiers in Cell and Developmental Biology, Vol: 6, ISSN: 2296-634X

A marked increase in the rate of glycolysis is a key event in the pathogenesis of hepatocellular carcinoma (HCC), the main type of primary liver cancer. Liver cirrhosis is considered to be a key player in HCC pathogenesis as it precedes HCC in up to 90% of patients. Intriguingly, the biochemical events that underlie the progression of cirrhosis to HCC are not well understood. In this study, we examined the expression profile of metabolic gene transcripts in liver samples from patients with HCC and patients with cirrhosis. We found that gene expression of glycolytic enzymes is up-regulated in precancerous cirrhotic livers and significantly associated with an elevated risk for developing HCC. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in HCC compared to normal livers but remain unchanged in cirrhosis. Our findings suggest that key glycolytic enzymes such as hexokinase 2 (HK2), aldolase A (ALDOA), and pyruvate kinase M2 (PKM2) may represent potential markers and molecular targets for early detection and chemoprevention of HCC.

Journal article

Papa S, Bubici C, 2018, Feeding the hedgehog: a new meaning for JNK signalling in liver regeneration, Journal of Hepatology, Vol: 69, Pages: 572-574, ISSN: 0168-8278

Journal article

Manka P, Coombes JD, Boosman R, Gauthier K, Papa S, Syn WKet al., 2018, Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment, Cancer Letters, Vol: 419, Pages: 175-186, ISSN: 0304-3835

Hepatocellular carcinoma (HCC) commonly arises from a liver damaged by extensive inflammation and fibrosis. Various factors including cytokines, morphogens, and growth factors are involved in the crosstalk between HCC cells and the stromal microenvironment. Increasing our understanding of how stromal components interact with HCC and the signaling pathways involved could help identify new therapeutic and/or chemopreventive targets. It has become increasingly clear that the cross-talk between tumor cells and host stroma plays a key role in modulating tumor growth. Emerging reports suggest a relationship between HCC and thyroid hormone signaling (dysfunction), raising the possibility that perturbed thyroid hormone (TH) regulation influences the cancer microenvironment and cancer phenotype. This review provides an overview of the role of thyroid hormone and its related pathways in HCC and, specifically, its role in regulating the tumor microenvironment.

Journal article

Verzella D, Bennett J, Fischietti M, Thotakura AK, Recordati C, Pasqualini F, Capece D, Vecchiotti D, D'Andrea D, Di Francesco B, De Maglie M, Begalli F, Tornatore L, Papa S, Lawrence T, Forbes SJ, Sica A, Alesse E, Zazzeroni F, Franzoso Get al., 2017, GADD45β loss ablates innate immunosuppression in cancer, Cancer Research, Vol: 78, Pages: 1275-1292, ISSN: 1538-7445

T cell exclusion from the tumour microenvironment (TME) is a major barrier to overcoming immune escape. Here we identify a myeloid-intrinsic mechanism governed by the NF-κB effector molecule GADD45β that restricts tumour-associated inflammation and T cell trafficking into tumours. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural immune infiltration, thereby diminishing oncogenesis. Our results provide a basis to interpret clinical evidence that elevated expression of GADD45B confers poor clinical outcomes in most human cancers. Further, they suggest a therapeutic target in GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.

Journal article

Briones MA, Coombes JD, Mellone M, Rispoli R, Tolosa E, Manka PP, Kitamura N, Quaglia A, Canbay A, Alpini G, Glaser SS, Williams R, Papa S, Fernandez-Zapico ME, Syn W-Ket al., 2016, The role of osteopontin isoforms in cholangiocarcinoma, 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY, Pages: 235A-235A, ISSN: 0270-9139

Conference paper

Papa S, Bubici C, 2016, Linking apoptosis to cancer metabolism: Another missing piece of JuNK, Molecular & Cellular Oncology, Vol: 3, ISSN: 2372-3556

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.

Journal article

Briones-Orta MA, Coombes JD, Mellone M, Rispoli R, Manka PP, Younis R, Kitamura N, Glaser SS, Alpini G, Quaglia A, Williams R, Papa S, Canbay A, Syn W-Ket al., 2015, Osteopontin-c isoform promotes a mesenchymal phenotype in human cholangiocarcinoma cells, 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 1171A-1171A, ISSN: 0270-9139

Conference paper

Papa S, Bubici C, 2015, Starving cancer cells of sugar could be the key to future treatment

Other

Iansante V, Choy PM, Fung SW, Liu Y, Chai J-G, Dyson J, Del Rio A, D'Santos C, Williams R, Chokshi S, Anders RA, Bubici C, Papa Set al., 2015, PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation, Nature Communications, Vol: 6, ISSN: 2041-1723

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.

Journal article

Coombes JD, Swiderska-Syn M, Dolle L, Reid D, Eksteen B, Claridge L, Briones-Orta MA, Shetty S, Oo YH, Riva A, Chokshi S, Papa S, Mi Z, Kuo PC, Williams R, Canbay A, Adams DH, Diehl AM, van Grunsven LA, Choi SS, Syn WKet al., 2015, Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice, GUT, Vol: 64, Pages: 1120-1131, ISSN: 0017-5749

Journal article

Iansante V, Choy PM, Chokshi S, Williams R, Anders RA, Bubici C, Papa Set al., Addressing the interplay between apoptosis and glucose metabolism in liver cirrhosis and HCC, Digestives Disorders Federation

Conference paper

Choy PM, Sufi J, Glaser S, Alpini G, Heaton N, Williams R, Quaglia A, Syn W-K, Bubici C, Papa Set al., 2015, INHIBITION OF MAPK SIGNALLING PROMOTES CELL CYCLE ARREST AND SENSITISES INTRAHEPATIC CHOLANGIOCARCINOMA CELLS TO CHEMOTHERAPY, 2nd Digestive-Disorders-Federation Conference, Publisher: BMJ PUBLISHING GROUP, Pages: A458-A458, ISSN: 0017-5749

Conference paper

Iansante V, Choy PM, Chokshi S, Williams R, Anders RA, Bubici C, Papa Set al., 2015, INCREASED AEROBIC GLYCOLYSIS IS ASSOCIATED WITH POOR OUTCOME AND SUPPRESSION OF APOPTOSIS IN HUMAN LIVER CIRRHOSIS AND HCC, 50th International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S427-S427, ISSN: 0168-8278

Conference paper

Iansante V, Choy PM, Fung SW, Chai J-G, Dyson J, Liu Y, Williams R, Chokshi S, Anders RA, Bubici C, Papa Set al., 2014, UPREGULATION OF A NOVEL PROTEIN IN HCC ENHANCES CANCER CELL SURVIVAL BY SUPPRESSING SPECIFIC APOPTOTIC EFFECTORS, 49th Annual International Liver Congress of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S89-S89, ISSN: 0168-8278

Conference paper

Bubici C, Papa S, 2014, JNK signalling in cancer: in need of new, smarter therapeutic targets, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 171, Pages: 24-37, ISSN: 0007-1188

Journal article

Briones-Orta MA, Coombes JD, Kitamura N, Manka PP, Williams R, Canbay A, Papa S, Syn W-Ket al., 2014, Osteopontin isoforms are upregulated in human cholangiocarcinoma cells and modulate levels of the TGF-beta repressor, SnoN, 65th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 818A-818A, ISSN: 0270-9139

Conference paper

Wang Z, Hou J, Lu L, Qi Z, Sun J, Gao W, Meng J, Wang Y, Sun H, Gu H, Xin Y, Guo X, Yang Get al., 2013, Small Ribosomal Protein Subunit S7 Suppresses Ovarian Tumorigenesis through Regulation of the PI3K/AKT and MAPK Pathways, PLOS ONE, Vol: 8, ISSN: 1932-6203

Journal article

Coombes J, Claridge LC, Swiderska-Syn M, Briones-Orta MA, Younis R, Shah H, Papa S, Diehl AM, Eksteen B, Canbay A, Syn W-Ket al., 2013, Osteopontin enhances liver progenitor cell responses in progressive Nonalcoholic Steatohepatitis, 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 535A-535A, ISSN: 0270-9139

Conference paper

Barbarulo A, Iansante V, Chaidos A, Naresh K, Rahemtulla A, Franzoso G, Karadimitris A, Haskard DO, Papa S, Bubici Cet al., 2013, Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma, ONCOGENE, Vol: 32, Pages: 4231-4242, ISSN: 0950-9232

Journal article

Iansante V, Zen Y, Barbarulo A, Starling C, Chokshi S, Heaton N, Williams R, Bubici C, Quaglia A, Papa Set al., 2012, MAPK SIGNALLING REGULATES THE DEVELOPMENT OF A CHOLANGIOCELLULAR PHENOTYPE FROM HCC IN POST-TACE LIVER TRANSPLANTS, 1st Combined Digestive Disorders Federation Meeting of the British-Society-of-Gastroenterology (BSG), Association-of-Upper-Gastrointestinal-Surgeons (AUGIS), BAPEN and British-Association-for-the-Study-of-the-Liver (BASL), Publisher: BMJ PUBLISHING GROUP, Pages: A416-A416, ISSN: 0017-5749

Conference paper

Iansante V, Zen Y, Barbarulo A, Starling C, Chokshi S, Heaton N, Williams R, Bubici C, Quaglia A, Papa Set al., 2012, MIXED-PHENOTYPE HEPATOCELLULAR CARCINOMA IN LIVER TRANSPLANTS AFTER USE OF TRANSARTERIAL CHEMOEMBOLIZATION (TACE) IS ASSOCIATED WITH ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) SIGNALLING PATHWAY, International Liver Congress / 47th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S117-S117, ISSN: 0168-8278

Conference paper

Svensson CI, Inoue T, Hammaker D, Fukushima A, Papa S, Franzoso G, Schett G, Corr M, Boyle DL, Firestein GSet al., 2009, Gadd45 beta Deficiency in Rheumatoid Arthritis Enhanced Synovitis Through JNK Signaling, ARTHRITIS AND RHEUMATISM, Vol: 60, Pages: 3229-3240, ISSN: 0004-3591

Journal article

Papa S, Bubici C, Zazzeroni F, Franzoso Get al., 2009, Mechanisms of liver disease: cross-talk between the NF-kappa B and JNK pathways, 4th International Conference of the Collaborative Research Center 575 Experimental Hepatology (SFB 575), Publisher: WALTER DE GRUYTER & CO, Pages: 965-976, ISSN: 1431-6730

Conference paper

Papa S, Bubici C, Zazzeroni F, Franzoso Get al., 2009, Mechanisms of liver disease: the crosstalk between the NF-kappaB and JNK pathways., Biol Chem, Vol: 390, Pages: 965-976

Abstract The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated or virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury specific intracellular processes are initiated to maintain the liver integrity. Inflammatory cytokines including tumor necrosis factor (TNF)alpha and interleukin-6 (IL-6) are key mediators of these processes as they can activate different cellular response like proliferation, survival and death. TNFalpha induces specific signaling pathways in hepatocytes leading to the activation of either pro-survival mediators or effectors of cell death. While the activation of transcription factor NF-kappaB promotes survival, the induction of c-Jun N-terminal kinases (JNKs) and caspases represent the strategic effectors of cell death in the TNFalpha-mediated signaling pathway. This review summarizes recent advances in the mechanisms of TNFalpha-induced hepatotoxicity, suggesting that NF-kappaB plays a protective role against JNK-induced hepatocyte death. The identification of mechanisms regulating the interplay between the NF-kappaB and JNK pathways is required to identify novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.

Journal article

Tumanov AV, Koroleva EP, Christiansen PA, Khan MA, Ruddy MJ, Burnette B, Papa S, Franzoso G, Nedospasov SA, Fu Y-X, Anders RAet al., 2009, T cell-derived lymphotoxin regulates liver regeneration., Gastroenterology, Vol: 136, Pages: 694-704.e4

BACKGROUND & AIMS: The ability of the liver to regenerate hepatic mass is essential to withstanding liver injury. The process of liver regeneration is tightly regulated by distinct signaling cascades involving components of the innate immune system, cytokines, and growth factors. However, the role of the adaptive immune system in regulation of liver regeneration is not well-defined. The role of adaptive immune system in liver regeneration was investigated in lymphocyte-deficient mice and in conditional lymphotoxin-deficient mice. METHODS: A model of liver regeneration after 70% partial hepatectomy was used, followed by examination of liver pathology, survival, DNA synthesis, and cytokine expression. RESULTS: We found that mice deficient in T cells show a reduced capacity for liver regeneration following partial hepatectomy. Furthermore, surface lymphotoxin, provided by T cells, is critical for liver regeneration. Mice specifically deficient in T-cell lymphotoxin had increased liver damage and a reduced capacity to initiate DNA synthesis after partial hepatectomy. Transfer of splenocytes from wild-type but not lymphotoxin-deficient mice improved liver regeneration in T cell-deficient mice. We found that an agonistic antibody against the lymphotoxin beta receptor was able to facilitate liver regeneration by reducing liver injury, increasing interleukin-6 production, hepatocyte DNA synthesis, and survival of lymphocyte-deficient (Rag) mice after partial hepatectomy. CONCLUSIONS: The adaptive immune system directly regulates liver regeneration via a T cell-derived lymphotoxin axis, and pharmacological stimulation of lymphotoxin beta receptor might represent a novel therapeutic approach to improve liver regeneration.

Journal article

Tornatore L, Montil SM, Marasco D, Dathan N, Vitale RM, Benedetti E, Pedone C, Papa S, Franzoso G, Ruvo Met al., 2009, Gadd45 beta dimerization does not affect MKK7 binding, 20th American-Peptide-Society Symposium, Publisher: SPRINGER, Pages: 367-368, ISSN: 0065-2598

Conference paper

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