Inhibiting cell metabolism to enhance tumour cell death

As you read this, millions of your cells from your body are dying. Do not panic – this is not bad news. Most of them are either superfluous or potentially harmful, so you are better off without them. In fact, your health depends on the astute use of a certain kind of programmed cell death, also known as apoptosis. However, this is bad news when it comes to treatment for human cancers with anti-cancer (chemo) drugs. For reason yet not clear certain cancer cells are resistant to death (apoptosis) induced by some chemo drugs. What’s more is that certain cancer types are also more addicted to glucose (sugar) for the maintenance of their survival.

More specifically, cancer cells possess a near-universal metabolic phenotype known as aerobic glycolysis (or the Warburg effect), which is characterised by the consumption of glucose to generate intermediary metabolites (precursors of nucleotides, proteins and lipids) and reducing equivalents (such as NADPH) required for the doubling of cellular biomass and to suppress apoptosis, respectively. Importantly, increased aerobic glycolysis provides cancer cells with an antioxidant defence against oxidative damage induced by certain anti-cancer drugs. Therefore, studies aimed at reducing the sugar addiction of cancer cells would be beneficial for developing new treatments.

Our group, in collaboration with Dr Salvatore Papa at University of Leeds, has conducted a series of interdisciplinary studies (Barbarulo et al., Oncogene 2013; Iansante et al., Nature Commun 2015; Lee et al., Front Cell Dev Biol. 2018) to investigate the intracellular mechanisms regulating cancer cell survival.

In this study we will examine whether drug-resistant and drug-sensitive cancer cells display distinct metabolic features and aim to do a series of laboratory experiments to investigate the ability of probes, or drugs, to starve cancer cells of glucose. If successful, this could lead to explore combination of drugs being tested in cancer patients.

References:

• Lee NCW, Carella MA, Papa S, Bubici C. High Expression of Glycolytic Genes in Cirrhosis Correlates With the Risk of Developing Liver Cancer. Front. Cell Dev. Biol. 6:138. (2018).
• 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 and Papa S. PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation. Nat Commun, 6: 7882 (2015).
• Bubici C and Papa S. JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol, 171: 24-37 (2014).
• Barbarulo A, Iansante V, Chaidos A, Naresh K, Rahemtulla A, Franzoso G, Karadimitris A, Haskard DO, Papa S & Bubici C. Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma. Oncogene, 32: 4231-4242 (2013). 

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