Faculty Collaboration Database

Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer. Cancer Res 2009 Feb 01;69(3):1063-70

Date

01/15/2009

Pubmed ID

19141650

Pubmed Central ID

PMC4403239

DOI

10.1158/0008-5472.CAN-08-1751

Scopus ID

2-s2.0-59149086648 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

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.

Author List

Wang H, Song X, Logsdon C, Zhou G, Evans DB, Abbruzzese JL, Hamilton SR, Tan TH, Wang H

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cell Growth Processes
Cell Line, Tumor
Cell Transformation, Neoplastic
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Disease Progression
Down-Regulation
Humans
Immunohistochemistry
Pancreatic Neoplasms
Proteasome Endopeptidase Complex
RNA, Messenger
Transfection