Fermented wheat germ extract modulates organic selenium availability to regulate programmed cell death and metabolic reprogramming through the ATM/ATR/p53 pathway.

BACKGROUND

Disruption of selenium homeostasis is closely associated with the development and progression of multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). Fermented wheat germ extract (FWGE) has demonstrated antitumor activity; however, the effects and underlying mechanisms of its combination with selenocysteine in PDAC remain unclear.

METHODS

The antitumor effects of FWGE and selenocysteine were systematically evaluated in human PDAC PANC-1 cells and a nude mouse subcutaneous xenograft model. Cell viability, apoptosis, migration, and invasion were assessed using CCK-8 assays, flow cytometry, and Transwell assays. Cellular energy metabolism was analyzed by Seahorse extracellular flux analysis, and intracellular selenium levels were determined by ICP-MS. Activation of the ATM/ATR/p53 pathway was examined by Western blot, and functional rescue experiments were performed via p53 overexpression. In vivo efficacy was evaluated by tumor growth measurement, Ki-67 immunohistochemistry, TUNEL staining, and Western blot analysis of tumor tissues.

RESULTS

FWGE or selenocysteine alone moderately inhibited PANC-1 cell proliferation, migration, and invasion and induced apoptosis, whereas combined treatment produced significantly enhanced antitumor effects. The combination markedly suppressed glycolytic activity and increased intracellular selenium accumulation. Mechanistically, combined treatment reduced the phosphorylation levels of ATM, ATR, and p53. p53 overexpression partially reversed the inhibitory effects of the combined treatment on malignant phenotypes, indicating functional involvement of p53 signaling. In vivo, combined FWGE and selenocysteine treatment significantly suppressed tumor growth, reduced Ki-67 expression, increased tumor cell apoptosis, and further decreased ATM/ATR/p53 phosphorylation compared with monotherapies.

CONCLUSION

Combined FWGE and selenocysteine treatment exerts pronounced antitumor effects against PDAC both in vitro and in vivo, potentially through modulation of cellular energy metabolism and inhibition of the ATM/ATR/p53 signaling pathway.