Exp Mol Med.  2004 Oct;36(5):493-498.

Involvement of mitogen-activated protein kinases and p21Waf1 in hydroxyurea-induced G1 arrest and senescence of McA-RH7777 rat hepatoma cell line

Affiliations
  • 1Division of Basic Science, National Cancer Center Research Institute, Goyang, Gyeonggi 411-769, Korea.
  • 2Department of Pathology, Dong-A University College of Medicine, Busan 602-714, Korea. jsjung1@daunet.donga.ac.kr
  • 3Medical Science Research Center, Dong-A University College of Medicine, Busan 602-714, Korea.
  • 4Department of Biochemistry, Dong-A University College of Medicine, Busan 602-714, Korea.
  • 5Department of Nursing, Masan College, Masan, Gyeongnam 639-720, Korea.

Abstract

Hydroxyurea is commonly used to treat hematologic disorders and some type of solid tumors, but the mechanism for its therapeutic effect is not clearly known. In this study, we examined the effect of hydroxyurea on rat hepatoma McA-RH7777 cells, specifically, on the role of mitogen-activated protein (MAP) kinase signal transduction pathways and p21Waf1, p27Kip1 and p53. Rat hepatoma McA-RH7777 cells treated with hydroxyurea for 7 days, caused the inhibition of cell growth in a dose-dependent manner. But, this growth inhibition was not caused by necrosis or apoptosis but instead was associated with cell senescence-like change as evidenced by senescence associated-beta-galactosidase staining, and cells arrest at G1 phase of cell cycle. Phosphorylation of MAP kinases, such as ERK, JNK, and p38, was found to be decreased after treatment of cells with hydroxyurea. But, the expression of p21Waf1 was increased, while p27Kip1 and p53 were not detected in hydroxyurea treated rat hepatoma cells. Hydroxyurea treatment induced G1 arrest and a senescence-like changes in rat hepatoma McA-RH7777 cells may be the likely results of signal disruption of MAP kinases (ERK, JNK, and p38 MAP kinase) and p21Waf1 over-expression.

Keyword

hydroxyurea; MAP kinases; p21Waf1; rat hepatoma cells

MeSH Terms

Animals
Antineoplastic Agents/*pharmacology
Cell Aging/drug effects
Cell Cycle Proteins/analysis/metabolism/*physiology
Cell Line, Tumor
Cell Proliferation/drug effects
G1 Phase/drug effects/physiology
Hydroxyurea/*pharmacology
Liver Neoplasms, Experimental/enzymology/*metabolism
Mitogen-Activated Protein Kinases/analysis/*physiology
Phosphorylation/drug effects
Protein p53/analysis/metabolism
Rats
Research Support, Non-U.S. Gov't
Tumor Suppressor Proteins/analysis/metabolism
Up-Regulation
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