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OUR SCIENCE BIT....FOR SPECIALISTS

MISSION 


We focus our research on understanding  the molecular mechanisms, regulation and role of apoptosis (i.e. programmed cell death) in pathogenesis, and translating these insights in therapeutic concepts and, if possible, novel treatments for human disease including cancer, inflammation and infectious disease.
 


RESEARCH LINES

In normal tissues there is a balance between the generation of new cells via cell division and the loss of cells via cell death. Old cells become damaged over time and are eliminated. The classical example include shedding of dead skin cells from the skin that are replaced by newly generated cells.  Like cell division, cell death is also tightly controlled. Hence, cells frequently die by a process termed programmed cell death or apoptosis (a Greek term meaning ‘falling off’, in reference to leaves falling off a tree). In biology, the term apoptosis refers to a form of 'programmed cell death'.

 

Aberrant apoptosis is critically involved in many debilitating or life-threatening diseases, including cancer, chronic inflammation and neurodegenerative disease. Moreover, inducing apoptosis has become a treatment option for certain cancers but current anti-cancer approaches face problems of intrinsic or acquired resistance that contribute to maintain cell survival.

 

Our research interests aim to investigate the molecular mechanisms regulating apoptosis in response to mitogenic signals such as pro-inflammatory cytokines and oncogenic stimuli. Specifically, we investigate the link between metabolism, cellular transformation and resistance to apoptosis.

 

RECENT FINDINGS AND TECHNOLOGICAL APPROACHES

During the last decade, we have devoted our research activity in studying the biological role of NF-kB transcription factors in normal and diseased states, and how alterations of its transcriptional activity contribute to human disease, including autoimmunity, chronic inflammation and cancer.

 

We have made important contributions to the fields of cell biology and apoptosis and our work has significantly advanced the understanding of the mechanisms by which NF-kB promotes cell survival and proliferation in response to pro-inflammatory signals. We have published seminal studies that spanned from the early gene discovery phase to further mechanistic characterisation and finally to the demonstration of biological relevance in animal models (three major research papers as a first author (De Smaele E et al., Nature 2001; Papa S. et al. Nat Cell Biol 2004; Papa S. et al. J Biol Chem 2007; Papa S. et al. J Clin Invest 2008). These studies have also contributed to the generation of two international patents (WO2003028659 A2 and EP1506784 A1), and are the scientific background behind the generation of novel anti-cancer drugs currently being tested in pre-clinical studies.

 

In more recent years, we have established a research team focussing on the identification and characterisation of novel kinases substrates. On this regard, our team's research program aims to explore the regulation and function of c-Jun N-terminal Kinase (JNK) and the molecular mechanisms by which each kinase isoform acts in malignant cells. We have recently shown that JNK2 is the only JNK isoform involved in pathogenesis of multiple myeloma, and that the poly(ADP-ribose) polymerase (PARP14), a key regulator of B-cell survival, acts as a specific downstream effector of the JNK2 signal pathway (Barbarulo A et al., Oncogene 2013; Bubici C and Papa S, Br J Pharmacol 2013).

 

These studies have benefited from a close collaboration with Dr Bubici at Brunel University London. We have further explored the role of the anti-apoptotic protein PARP14 in the regulation of metabolic program (aerobic glycolysis, also known as Warburg effect) in a variety of proliferating cells, including pre-cancerous and cancerous cells. A manuscript reporting these findings has been recently published in Nature Communications (Iansante et al., 2015). 

Using loss-of-function studies in vitro and in vivo, we have showed that PARP14 is an important determinant of the Warburg effect in most proliferating tumour cells, including hepatoma, breast carcinoma, brain glioma, gastric carcinoma and myeloma. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 (a key glycolytic enzyme) through phosphorylation of Thr365. Using this mechanism, PARP14 suppresses the metabolic activity of PKM2 leading to enhanced glycolysis, and thus demonstrating a link between suppression of apoptosis and altered metabolism in cancer cells.

These studies place PARP14 at the center of a hub regulating energy metabolism and cancer cell survival, making it a possible molecular target in cancer therapy. These mechanistic representations allow functional prediction of the effect of blockage of metabolic pathways in cancer cells via PARP14 inhibition. Pre-clinical validation of the findings is performed using genetic or pharmacological inhibition of PARP14 in in-vitro and in-vivo tumour models.

PARP14 at the center of a hub regulating energy metabolism and cancer cell survival

Source: "Linking apoptosis to cancer metabolism: Another missing piece of JuNK" Mol Cell Oncol. 2016; 3:e1103398. 

 

Major signaling pathways in glycolytic cancers. Schematic illustration of the intracellular pathways activated in glycolytic cancer cells. Green line: oncogenic stimuli promote the overexpression of tumor initiating molecules (i.e., PARP14). Red line: accumulation of cellular stress activates the JNK cascade that consists of mitogen-activating protein kinase kinase kinase (MAP3K), which in turn phosphorylates and activates mitogen-activated protein kinase kinase 7 (MKK7), a direct activator of JNK. Blue line: cancer cells are fuelled by glucose, which is transported into the cells via glucose transporters (GLUT). Much of the intracellular glucose is converted into lactate by glycolytic enzymes, the most important ones being hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase isozyme type M2 (PKM2). The high levels of PARP14 observed in cancer cells halt JNK1-mediated phosphorylation of downstream substrates (i.e., PKM2), thus maintaining low PKM2 activity. Consequently, there is an accumulation of upstream glycolytic intermediates that favors the synthesis of cellular building blocks (i.e., amino acid, lipids, nucleotides) that are used to generate daughter cells. During the branching of these synthetic pathways, antioxidants are also produced to counteract the cell-damaging products (i.e., reactive oxygen species [ROS]). In the event of failure to halt JNK1-mediated phosphorylation and activation of PKM2, cancer cells die by apoptosis as a result of enhanced accumulation of intracellular ROS.

Lately, we have also focused our attention in human cancers in urgent need of treatment options, such as intrahepatic cholangiocarcinoma (ICC), a form of bile duct cancer. Aberrant activation of the JNK pathway is a key feature in intrahepatic cholangiocarcinoma (ICC) – a highly aggressive type of liver cancer in urgent need of treatment options – and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and therefore the key downstream effectors of this pathway, remain unknown for their applicability as therapeutic targets. In a seminal publication in HEPATOLOGY (Lepore et al. Hepatology 2021), we have demonstrated that the constitutive activation of JNK leads to elevated levels of PIN1 expression, thus promoting ICC cell proliferation. We show that JNK proteins directly interact with and phosphorylate PIN1 at Ser115. The phosphorylation of PIN1 at this specific residue directly causes the increase in intracellular PIN1 levels by preventing its mono-ubiquitination at Lys117, and, consequently, inhibiting its proteasomal degradation. 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 through PIN1 inhibition. Indeed, we also show the potential application of PIN1 inhibition using all-trans retinoic acid (ATRA) for ICC therapy. 

Designed by the author using illustrations provided by Servier under CC BY 3.0  License (http://smart.servier.com).

 

Cartoon depicting the front view of the liver and gallbladder within the gastrointestinal system. Also shown is the small intestine with whom the liver and gallbladder have an intricate connection. The gallbladder collects the bile produced by the liver through small tubes (or canaliculi) called bile ducts. After meals, the gallbladder is emptied and squeezes bile into the small intestine to digest mainly fats. Bile duct cancer develops from the uncontrolled proliferation of corrupted cholangiocytes, the endothelial cells lining the bile ducts. This uncontrolled proliferation is allowed by the expression of oncogenic signals such as the expression of PIN1. Pharmacological inhibition of PIN1 via administration of drugs such as ATRA could shrink bile duct tumours.

To learn more read our latest articles in HEPATOLOGY and The Conversation UK

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