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The pancreas is a mixed gland primarily composed of exocrine tissue, which secretes digestive enzymes into the digestive tract, and an endocrine component organized into small clusters known as islets of Langerhans, constituting approximately 1% of the pancreatic mass. Each adult islet contains an average of 1,500 cells, including beta-, alpha- and delta-cells, which produce and secrete insulin (INS), glucagon (GCG), and somatostatin (SST) respectively. The destruction of insulin-producing beta-cells or the defective insulin secretion give rise to type 1 and type 2 diabetes mellitus, respectively. These chronic metabolic disorders are characterized by the dysregulation of glucose homeostasis. The pathophysiology of diabetes has been extensively studied and beta-cell biology is now described in great details. Glucose is taken up by beta-cells, metabolized and generates an increase in the intracellular ATP:ADP ratio that drives the closure of ATP-sensitive potassium (KATP) channels. This causes membrane depolarization, leading to the activation of voltage-gated calcium channels, which increases intracellular calcium level and initiates insulin secretion. This secretory process is enhanced by signals mediated by insulinotropic Gαs coupled G Protein Coupled Receptors (GPCRs) that increase cAMP levels. For example, this occurs through GCG-, Glucagon-like Peptide 1- (GLP1) and Glucose-dependent insulinotropic polypeptide (GIP)-Receptors, all of which are expressed at the beta-cell surface. In parallel, SST secreted by delta-cells, by acting through its receptors expressed on beta-cells, decreases cAMP levels and insulin secretion. Drugs targeting beta-cell secretion are used to treat patients suffering of type 2 diabetes. They increase insulin secretion by closing the KATP channels (sulfonylureas) or by increasing intracellular cAMP (GLP1R agonists). However, many aspects of pancreatic islet function remain to be further understood. Specifically, more needs to be learned about the role of signals from alpha- and delta-cells on beta-cells within the islets.

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A non-proliferative role of pyrimidine metabolism in cancer

Aarif Siddiqui, Paolo Ceppi

Background

Nucleotide metabolism is a critical pathway that generates purine and pyrimidine molecules for DNA replication, RNA synthesis, and cellular bioenergetics. Increased nucleotide metabolism supports uncontrolled growth of tumors and is a hallmark of cancer. Agents inhibiting synthesis and incorporation of nucleotides in DNA are widely used as chemotherapeutics to reduce tumor growth, cause DNA damage, and induce cell death. Thus, the research on nucleotide metabolism in cancer is primarily focused on its role in cell proliferation. However, in addition to proliferation, the role of purine molecules is established as ligands for purinergic signals. However, so far, the role of the pyrimidines has not been discussed beyond cell growth.

Scope of the review

In this review we present the key evidence from recent pivotal studies supporting the notion of a non-proliferative role for pyrimidine metabolism (PyM) in cancer, with a special focus on its effect on differentiation in cancers from different origins.

Major conclusion

In leukemic cells, the pyrimidine catabolism induces terminal differentiation toward monocytic lineage to check the aberrant cell proliferation, whereas in some solid tumors (e.g., triple negative breast cancer and hepatocellular carcinoma), catalytic degradation of pyrimidines maintains the mesenchymal-like state driven by epithelial-to-mesenchymal transition (EMT). This review further broadens this concept to understand the effect of PyM on metastasis and, ultimately, delivers a rationale to investigate the involvement of the pyrimidine molecules as oncometabolites. Overall, understanding the non-proliferative role of PyM in cancer will lead to improvement of the existing antimetabolites and to development of new therapeutic options.