Pancreatic stellate cells regulate branched-chain amino acid metabolism in pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy: it has a 5-year survival rate of less than 9%. Although surgical resection is an effective treatment for PDAC, only a small number of patients can have their tumors surgically removed. Thus, an urgent need to find new therapeutic targets for PDAC exists. Understanding the molecular mechanism of PDAC development is essential for the treatment of this malignancy. This research aimed to study the mechanisms of pancreatic stellate cells (PSCs), which regulate branched-chain amino acid (BCAA) metabolism in PDAC.

Methods: Differentially expressed proteins were detected via nanoliquid chromatography coupled to mass spectrometry (nano-LC-MS/MS). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment methods were used to find the valine-leucine-isoleucine (BCAA) degradation pathway. The levels of BCAAs in the sera and tissues of patients with PDAC were measured by using nuclear magnetic resonance (NMR). The functions of BCAA concentrations and the effects of activated pancreatic stellate cells (aPSCs) were also evaluated by performing Cell Counting Kit-8, colony formation, and wound healing assays.

Results: A total of 1,519 proteins with significantly differential expression were discovered in PDAC and adjacent tissues by using nano-LC-MS/MS. KEGG pathway enrichment analysis identified the BCAA degradation pathway. The content of BCAA in PDAC clinical samples was up-regulated. However, the addition of different concentrations of BCAA to PDAC cell culture medium failed to promote the proliferation and migration of PDAC cells. Given that analysis based on The Cancer Genome Atlas database showed that the number of aPSCs gradually increased with the progression of PDAC, the effects of aPSCs on PDAC cells were explored. After coculture with aPSCs, PDAC cell proliferation showed a significant increase, and the proteins involved in the BCAA degradation pathway in PDAC cells had also changed.

Conclusions: aPSCs could regulate BCAA metabolism to enhance the progression of PDAC, indicating that the regulation of BCAA metabolism may serve as a new therapeutic direction for PDAC.