METABOLIC REPROGRAMMING IN CANCER

Reprogramming of cellular metabolism has been recently recognized as a hallmark of cancer.

A significant amount of glycolytic carbon is redirected into the synthesis of serine in a subset of human tumors, including breast cancer and melanoma. Moreover, changes in the serine/glycine metabolism is crucial for the development of tumor-initiating cells in non-small cells lung cancer (NSCLC). The metabolic shift of glycolytic carbon into serine anabolism drives the de novo biosynthesis of purines and pyrimidines that is required by highly proliferating cells (Amelio et al 2014 Trends in Biochem Sci, 39:191-8). Central to the aforementioned series of interconnected metabolic pathways is the conversion of serine to glycine, catalysed by the enzyme serine hydroxymethyltransferase (SHMT). This reaction represents a major source of methyl groups for the one-carbon pools that are required for the de novo nucleotide biosynthesis, and for DNA methylation. Therefore, SHMT occupies a critical position at the convergence of two key pathways for chemotherapeutic intervention: serine/glycine metabolism and nucleotide biosynthesis.

Despite the recent renewed interest in targeting enzymes of serine, folate and nucleotide metabolism and the endurance of drug-resistance in chemotherapeutic intervention, the paucity of recent studies focusing on inhibition of SHMT corroborates the feeling that this enzyme has still to be regarded as a missing target in cancer chemotherapy.

Our aim is to assess the role of serine metabolism and SHMT in metabolic reprogramming and energetic metabolism of cancer cells. We have  shown that SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation (Paone et al 2014, Cell Death Dis.,5:e1525). Our recent determination of the crystal structure of human mitochondrial SHMT2 and solution studies comparing the PLP-dependence of the aggregation state of both cytosolic and mitochondrial SHMTs have suggested important differences between the two isoforms (Giardina et al., FEBS J. 2015 Apr;282(7):1225-41.).

Moreover, we wish to evaluate the potential of SHMT inhibition to reverse the cancer cell anabolism of serine. Following preliminary evidences, we are currently working on antifolates (Daidone et al. 2011, Eur. J. Med. Chem, 46:1616-21, Paiardini et al. 2015 Mar;10(3):490-7.) and exploring novel compounds (Marani et al., Oncotarget. 2016 Jan 26;7(4):4570-83).

More recently, we are also investigating the link between infection, inflammation and metabolic reprogramming in prostate cancer, the   most common malignancy in men and a major cause of cancer deaths (Cutruzzolà et al. 2017 Front. Physiol. 8:97.)

 

Cancer