Imperial College London

DrConcettaBubici

Faculty of MedicineFaculty of Medicine Centre

Honorary Clinical Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 8432c.bubici

 
 
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Location

 

10.N6Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

41 results found

Lepore A, Choy PM, Lee NC, Carella MA, Favicchio R, Briones-Orta MA, Glaser SS, Alpini G, D'Santos C, Tooze RM, Lorger M, Syn W-K, Papakyriakou A, Giamas G, Bubici C, Papa Set al., 2021, Phosphorylation and stabilization of PIN1 by JNK promote intrahepatic cholangiocarcinoma growth, Hepatology, ISSN: 0270-9139

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and thus the key downstream effectors of this pathway remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signalling in ICC that could open new therapeutic opportunities. APPROACH AND RESULTS: Using loss- and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumours, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 via all-trans retinoic acid (ATRA), an FDA-approved drug, impairs the growth of both cultured and xenografted ICC cells. CONCLUSIONS: Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation via PIN1 inhibition.

Journal article

Bubici C, Lepore A, Papa S, 2019, ASKing no more: the emerging role of DUSP12 in the regulation of hepatic lipid metabolism, Hepatology, Vol: 70, Pages: 1091-1094, 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

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

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

Iansante V, Choy PM, Chokshi S, Williams R, Anders RA, Bubici C, Papa Set al., 2015, 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

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

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 GMBH, 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

Mauro C, Zazzeroni F, Papa S, Bubici C, Franzoso Get al., 2009, The NF-kappaB transcription factor pathway as a therapeutic target in cancer: methods for detection of NF-kappaB activity., Methods Mol Biol, Vol: 512, Pages: 169-207, ISSN: 1064-3745

NF-kappaB transcription factors marshal innate and adaptive immunity and inflammation. NF-kappaB also counters programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)alpha, and this activity of NF-kappaB is crucial for organismal physiology, chronic inflammation, and tumorigenesis. Indeed, whereas NF-kappaB contributes to many aspects of oncogenesis, it is now clear that its suppressive action on PCD is central to this process. Notably, recent studies indicate that NF-kappaB represents a crucial link in the well-established association between inflammation and carcinogenesis. In this link, NF-kappaB promotes synthesis of inflammatory mediators (e.g. TNFalpha) that stimulate growth of cancer cells, and upregulates genes that protect these cells against PCD induced by inflammatory signals. Elevated NF-kappaB activity also hampers tumor-cell killing inflicted by radiation and chemotherapeutic drugs, and in so doing, promotes resistance to anticancer therapy. Accordingly, NF-kappaB-targeting drugs are increasingly being used for treatment of human malignancies. Owing to the ubiquitous nature of the NF-kappaB pathway, however, these drugs have serious side effects, which limit their clinical use. Thus, a preferable approach would be to block, rather than NF-kappaB itself, its critical downstream targets that mediate discrete functions in cancer, such as prosurvival functions. Recent discoveries unraveling tissue specificity in the NF-kappaB-inducible mechanism(s) for control of PCD and identifying putative effectors of this control clearly validate this therapeutic approach. Given the emerging role of TNFkappa-induced signals of NF-kappaB activation in cancer and the potential of these signals for yielding new anticancer therapies, we focus herein on the methods most commonly used for analysis of the molecular steps leading from the triggering of TNF-Receptor (TNF-R)1 - the primary receptor of TNFalpha - to the induction of NF-kapp

Journal article

Papa S, Zazzeroni F, Fu YX, Bubici C, Alvarez K, Dean K, Christiansen P, Anders RA, Franzoso Get al., 2008, Gadd45{beta} promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling, J Clin Invest, Vol: 118, Pages: 1911-1923

In the liver, the JNK cascade is induced downstream of TNF receptors (TNFRs) in response to inflammatory, microbial, and toxic challenges. Sustained activation of JNK triggers programmed cell death (PCD), and hepatocyte survival during these challenges requires induction of the NF-kappaB pathway, which antagonizes this activation by upregulating target genes. Thus, modulation of JNK activity is crucial to the liver response to TNFR-mediated challenge. The basis for this modulation, however, is unknown. Here, we investigated the role of the NF-kappaB target Gadd45{beta} in the regulation of hepatocyte fate during liver regeneration after partial hepatectomy. We generated Gadd45b(-/-) mice and found that they exhibited decreased hepatocyte proliferation and increased PCD during liver regeneration. Notably, JNK activity was markedly increased and sustained in livers of Gadd45b(-/-) mice compared with control animals after partial hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK activity, completely rescued the regenerative response in Gadd45b(-/-) mice. Interestingly, Gadd45{beta} ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges. These data provide a basis for JNK suppression during liver regeneration and identify Gadd45{beta} as a potential therapeutic target in liver diseases.

Journal article

Papa S, Monti SM, Vitale RM, Bubici C, Jayawardena S, Alvarez K, De Smaele E, Dathan N, Pedone C, Ruvo M, Franzoso Get al., 2007, Insights into the structural basis of the Gadd45ß mediated inactivation of the JNK kinase, MKK7, J Chem Biol, Vol: 282, Pages: 19029-19041

NF-B/Rel factors control programmed cell death (PCD), and this control is crucial to oncogenesis, cancer chemoresistance, and antagonism of tumor necrosis factor (TNF) -induced killing. With TNF, NF-B-mediated protection involves suppression of the c-Jun-N-terminal kinase (JNK) cascade, and we have identified Gadd45, a member of the Gadd45 family, as a pivotal effector of this activity of NF-B. Inhibition of TNF-induced JNK signaling by Gadd45 depends on direct targeting of the JNK kinase, MKK7/JNKK2. The mechanism by which Gadd45 blunts MKK7, however, is unknown. Here we show that Gadd45 is a structured protein with a predicted four-stranded -sheet core, five -helices, and two acidic loops. Association of Gadd45 with MKK7 involves a network of interactions mediated by its putative helices 3 and 4 and loops 1 and 2. Whereas 3 appears to primarily mediate docking to MKK7, loop 1 and 4-loop 2 seemingly afford kinase inactivation by engaging the ATP-binding site and causing conformational changes that impede catalytic function. These data provide a basis for Gadd45-mediated blockade of MKK7, and ultimately, TNF-induced PCD. They also have important implications for treatment of widespread diseases.

Journal article

Kuntzen C, Zazzeroni F, Pham CG, Papa S, Bubici C, Knabb JR, Franzoso Get al., 2007, A method for isolating prosurvival targets of NF-κB/Rel transcription factors., Methods Mol. Biol., Vol: 399, Pages: 99-124

Journal article

Pham CG, Bubici C, Zazzeroni F, Knabb JR, Papa S, Kuntzen C, Franzoso Get al., 2007, Upregulation of Twist-1 by NF-kB blocks cytotoxicity induced by chemotherapeutic drugs, Mol Cell Biol, Vol: 27, Pages: 3920-3935

NF-B/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-B blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-B is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-B has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-B inhibits PCD triggered by chemotherapeutic drugs, however, remains poorly understood. To understand this mechanism, we sought to identify unrecognized protective genes that are regulated by NF-B. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-B. Twist-1 is an evolutionarily conserved target of NF-B, blocks PCD induced by chemotherapeutic drugs and TNF- in NF-B-deficient cells, and is essential to counter this PCD in cancer cells. The protective activity of Twist-1 seemingly halts PCD independently of interference with cytotoxic JNK, p53, and p19ARF signaling, suggesting that it mediates a novel protective mechanism activated by NF-B. Indeed, our data indicate that this activity involves a control of inhibitory Bcl-2 phosphorylation. The data also suggest that Twist-1 and -2 play an important role in NF-B-dependent chemoresistance.

Journal article

Bubici C, Papa S, Dean K, Franzoso Get al., 2006, Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance, ONCOGENE, Vol: 25, Pages: 6731-6748, ISSN: 0950-9232

Journal article

Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, Bubici C, Mossman BT, Pass HI, Testa JR, Franzoso G, Carbone Met al., 2006, TNF-alpha inhibits asbestos induced cytotoxicity via a NF-kappa B dependent pathway: A possible mechanism for asbestos-induced oncogenesis, LUNG CANCER, Vol: 54, Pages: S21-S21, ISSN: 0169-5002

Journal article

Yang H, Bocchetta M, Kroczynska B, Elmishad AG, Chen Y, Liu Z, Bubici C, Mossman BT, Pass HI, Testa JR, Franzoso G, Carbone Met al., 2006, TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappa B-dependent pathway, a possible mechanism for asbestos-induced oncogenesis, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 103, Pages: 10397-10402, ISSN: 0027-8424

Journal article

Papa S, Bubici C, Zazzeroni F, Pham CG, Kuntzen C, Knabb JR, Dean K, Franzoso Get al., 2006, The NF-kappa B-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease, CELL DEATH AND DIFFERENTIATION, Vol: 13, Pages: 712-729, ISSN: 1350-9047

Journal article

Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso Get al., 2006, The NF-kappa B-mediated control of ROS and JNK signaling, HISTOLOGY AND HISTOPATHOLOGY, Vol: 21, Pages: 69-80, ISSN: 0213-3911

Journal article

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