Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review

SIMPLE SUMMARY: Metabolic rewiring is now considered a hallmark of cancer. Pancreatic ductal adenocarcinoma (PDAC) extensively rewires its metabolism especially for the utilization of glucose and glutamine that are mainly used to provide the biosynthetic intermediates for nucleotides, protein, and lipid synthesis and for redox homeostasis. In this regard, mitochondrial solute carriers play a key role in metabolic compartmentalization and hence metabolic rewiring. At least five mitochondrial transporters are involved in the metabolic reprogramming of PDAC. Targeting these transporters may provide an attractive strategy to combat this aggressive cancer. This review dissects the current knowledge about the role of these transporters in PDAC in order to explore the therapeutic potential of their targeting. ABSTRACT: Pancreatic cancer is among the deadliest cancers worldwide and commonly presents as pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming is a hallmark of PDAC. Glucose and glutamine metabolism are extensively rewired in order to fulfil both energetic and synthetic demands of this aggressive tumour and maintain favorable redox homeostasis. The mitochondrial pyruvate carrier (MPC), the glutamine carrier (SLC1A5_Var), the glutamate carrier (GC), the aspartate/glutamate carrier (AGC), and the uncoupling protein 2 (UCP2) have all been shown to influence PDAC cell growth and progression. The expression of MPC is downregulated in PDAC and its overexpression reduces cell growth rate, whereas the other four transporters are usually overexpressed and the loss of one or more of them renders PDAC cells unable to grow and proliferate by altering the levels of crucial metabolites such as aspartate. The aim of this review is to comprehensively evaluate the current experimental evidence about the function of these carriers in PDAC metabolic rewiring. Dissecting the precise role of these transporters in the context of the tumour microenvironment is necessary for targeted drug development.