EGFR-induced phosphorylation of type Iγ phosphatidylinositol phosphate kinase promotes pancreatic cancer progression

Pancreatic cancer is one of the deadliest malignancies and effective treatment has always been lacking. In current study, we investigated how the type I. phosphatidylinositol phosphate kinase (PIPKI gamma) participates in the progression of pancreatic ductal adenocarcinoma (PDAC) for novel therapeutic potentials against this lethal disease. We found that PIPKI gamma is up-regulated in all tested PDAC cell lines. The growth factor (including EGFR)-induced tyrosine phosphorylation of PIPKI gamma is significantly elevated in in situ and metastatic PDAC tissues. Loss of PIPKI gamma inhibits the aggressiveness of PDAC cells by restraining the activities of AKT and STAT3, as well as MT1-MMP expression. Therefore when planted into the pancreas of nude mice, PIPKI gamma-depleted PDAC cells exhibits substantially repressed tumor growth and metastasis comparing to control PDAC cells. Results from further studies showed that the phosphorylation-deficient PIPKI gamma mutant, unlike its wild-type counterpart, cannot rescue PDAC progression inhibited by PIPK gamma depletion. These findings indicate that PIPKI gamma, functioning downstream of EGFR signaling, is critical to the progression of PDAC, and suggest that PIPKI gamma is potentially a valuable therapeutic target for PDAC treatment.