Adapting cellular riboflavin transport and metabolism in pancreatic ductal adenocarcinoma

Riboflavin (Rf) is an essential dietary component and is the precursor of FMN and FAD, the redox enzymatic cofactors required for mitochondrial terminal metabolism 1. Alterations in flavin homeostasis are associated with several pathological conditions, among which neuromuscular disorders 2 and cancer 3. We have recently demonstrated that transcription/translation of Rf transporters (RFVTs) are profoundly altered in colorectal cancer and we proposed that cancer cells need large amounts of Rf 4. Based on these evidences, we studied aspects related to flavin homeostasis in pancreatic ductal adenocarcinoma (PDAC) cells, comparing RFVT expression, the synthesis of FAD, and the amount of the mitochondrial flavoprotein, SDHA, in PANC-1 and in PANC-1 derived cancer stem cells (CSCs), which are expected to be metabolically plastic and malignant 5. As a control, we used HPDE (Human Pancreatic Ductal Epithelioid) cells which exhibit a gene expression pattern that more consistently resembles normal cell phenotype rather than cancerous ductal cells 6. The results obtained show that SDHA levels and flavin homeostasis are altered in tumour cells compared to HPDE, and that CSCs have higher rate of synthesis of flavin cofactors. These data favour the hypothesis that the metabolic pathway responsible for FAD synthesis could represent a new therapeutic target to reduce the proliferation of CSCs.