Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells

Tomomi Kogiso; Hikaru Nagahara; Etsuko Hashimoto; Shunichi Ariizumi; Masakazu Yamamoto; Keiko Shiratori

doi:10.1371/journal.pone.0100495

Efficient induction of apoptosis by wee1 kinase inhibition in hepatocellular carcinoma cells

PLoS One. 2014 Jun 24;9(6):e100495. doi: 10.1371/journal.pone.0100495. eCollection 2014.

Authors

Tomomi Kogiso¹, Hikaru Nagahara², Etsuko Hashimoto¹, Shunichi Ariizumi³, Masakazu Yamamoto³, Keiko Shiratori¹

Affiliations

¹ Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women's Medical University, Tokyo, Japan.
² Aoyama hospital, Tokyo Women's Medical University, Tokyo, Japan.
³ Institute of Gastroenterology, Department of Surgery, Tokyo Women's Medical University, Tokyo, Japan.

Abstract

Transforming growth factor-β1 (TGF-β1) potently inhibits human hepatocellular carcinoma (HCC) cell growth. Here we demonstrated that TGF-β1-induced apoptosis is mediated by decreased phosphorylation of cdc2 at Tyr15 accompanied by down-regulation of Wee1 kinase expression. As expected from these results, a Wee1 kinase inhibitor efficiently induced apoptosis in HCC cells in the absence of TGF-β1 treatment. In surgically resected samples, Wee1 kinase was expressed in moderately to poorly differentiated HCC, whereas no Wee1 kinase expression was observed in non-cancerous tissue, including cirrhotic tissue. Our results suggest that Wee1 kinase inhibitors may be a practical novel therapeutic option against advanced HCC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects*
CDC2 Protein Kinase
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cyclin-Dependent Kinases / metabolism
Enzyme Activation / drug effects
Gene Expression
Humans
Immunohistochemistry
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
RNA Interference
Transforming Growth Factor beta1 / pharmacology

Substances

Cell Cycle Proteins
Nuclear Proteins
Protein Kinase Inhibitors
Transforming Growth Factor beta1
Protein-Tyrosine Kinases
WEE1 protein, human
CDC2 Protein Kinase
CDK1 protein, human
Cyclin-Dependent Kinases

Grants and funding

Support for this study was received from Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (#26461024-0001), a Nakayama Cancer Research Institute Scholarship, an Itoe Okamoto Scholarship Grant, the Hisako Yamakawa Award and the Takako Satake Award at Tokyo Women's Medical University to T.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.