High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway.

PURPOSE: Diabetes mellitus is a critical risk factor for pancreatic cancer, yet its underlying molecular mechanism remains unclear. This study aims to investigate whether high glucose levels promote pancreatic cancer progression, and its molecular mechanism.

METHODS

Tumor samples were collected from pancreatic cancer patients with diabetes mellitus (DM + PC). Additionally, pancreatic cancer animal models were constructed with diabetes/high glucose feeding and high glucose cell culture medium. The expression of p-AMPK, p-DRP1(Ser616), and mitochondrial fission were evaluated through molecular analysis. The levels of lactic acid, H3K18la, TTK, and BUB1B were also evaluated.

RESULT: Survival analysis indicated that the clinical DM + PC group exhibited significantly worse overall survival (p < 0.05) and expressed significantly elevated levels of p-DRP1(Ser616) and HSP60 (p < 0.05). In the pancreatic cancer animal model with diabetes mellitus, higher tumor volumes and weights were observed along with elevated levels of p-DRP1(Ser616) and HSP60 (p < 0.05). Additionally, the high-glucose medium promoted proliferation and migration in cell lines (p < 0.05) and led to an increased expression of H3K18la, TTK, and BUB1B in a dose-dependent manner (p < 0.05). High levels of H3K18la, L-lactyl lysine, and TTK/BUB1B were expressed in DM + PC group(p < 0.05).

CONCLUSION

High glucose increases the expression of p-DRP (Ser616) by inhibiting p-AMPK and subsequently affecting mitochondrial fission and lactic acid levels. This process is likely prompted by lactation levels of histone H3 and the expression of BUB1B and TTK.