Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. In this study, we examined the expression, regulation, and functions of HPK1 in pancreatic ductal
adenocarcinomas (PDA). We found that loss of HPK1
protein expression correlated significantly with the progression of pancreatic intraepithelial
neoplasias (P = 0.001) and development of invasive PDA. Similarly, HPK1
protein was not expressed in any of eight PDA cell lines examined but was expressed in immortalized human pancreatic duct epithelial (HPDE) cells. There was no difference in HPK1
mRNA levels in PDA cell lines or primary PDA compared with those in HPDE cells or ductal epithelium in
chronic pancreatitis and normal pancreas, respectively. Treatment of Panc-1 cells with a
proteasome inhibitor,
MG132, increased the HPK1
protein levels in a dose-dependent manner, suggesting that alteration in
proteasome activity contributes to the loss of HPK1
protein expression in
pancreatic cancer. Like the endogenous HPK1, both wild-type HPK1 and its
kinase-dead mutant, HPK1-M46, overexpressed in Panc-1 cells, were also targeted by
proteasome-mediated degradation. After
MG132 withdrawal, wild-type HPK1
protein expression was markedly decreased within 24 hours, but
kinase-dead HPK1
mutant protein expression was sustained for up to 96 hours. Therefore,
HPK1 kinase activities were required for the loss of HPK1
protein in PDAs. Furthermore, restoring wild-type HPK1
protein in PDA cells led to the increase in p21 and p27
protein expression and cell cycle arrest. Thus, HPK1 may function as a novel
tumor suppressor and its loss plays a critical role in
pancreatic cancer.