Specific inhibitor of mek-mediated cross-talk between erk and p38 mapk during differentiation of human osteosarcoma cells

Tsuyoshi Shimo, Shinsuke Matsumura, Soichiro Ibaragi, Sachiko Isowa, Koji Kishimoto, Hiroshi Mese, Akiyoshi Nishiyama, Akira Sasaki

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Osteosarcoma is the most common primary malignant bone tumor, accounting for approximately 20% of all primary sarcomas in bone. Although treatment modalities have been improved over the past decades, it is still a tumor with a high mortality rate in children and young adults. Based on histological considerations, osteo-sarcoma arises from impaired differentiation of these immature cells into more mature types and that correction of this impairment may reduce malignancy and increase the efficiency of chemotherapy. The purpose of this study was to determine the effect of specific inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK) and p38 on the differentiation of human osteosar-coma cell line SaOS-2 cells. We found that PD98059, a specific inhibitor of MEK, inhibited the serum-stimulated proliferation of SaOS-2 cells; whereas SB203580, a specific inhibitor of p38 MAPK, had little effect on it. SB203580 suppressed ALPase activity, gene expression of type I collagen, and expression of ALP and BMP-2 mRNAs; whereas PD98059 upregulated them dose depen-dently. In addition, immunoblot and immunostaining analysis revealed that phosphorylation of ERK was increased by treatment with SB203580; whereas PD98059 increased the phosphorylation of p38, which implies a seesaw-like balance between ERK and p38 phosphoryla-tion. We suggest that osteosarcoma cell differentiation is regulated by the balance between the activities of the ERK and p38 pathways and that the MEK/ERK pathway negatively regulates osteosarcoma cell differentiation, whereas the p38 pathway does so positively. MEK inhibitor may thus be a good candidate for altering the expression of the osteosarcoma malignant phenotype.

Original languageEnglish
Pages (from-to)103-111
Number of pages9
JournalJournal of Cell Communication and Signaling
Volume1
Issue number2
DOIs
Publication statusPublished - 2007

Fingerprint

Osteosarcoma
Mitogen-Activated Protein Kinase Kinases
Phosphotransferases
Cell Differentiation
Phosphorylation
Sarcoma
Tumors
MAP Kinase Kinase Kinases
Bone
Bone and Bones
Neoplasms
Cells
MAP Kinase Signaling System
p38 Mitogen-Activated Protein Kinases
Coma
Collagen Type I
Chemotherapy
Young Adult
Gene expression
Phenotype

Keywords

  • Differentiaton
  • Extracellular signal-regulated kinase
  • Mitogen-activated protein kinase

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Specific inhibitor of mek-mediated cross-talk between erk and p38 mapk during differentiation of human osteosarcoma cells. / Shimo, Tsuyoshi; Matsumura, Shinsuke; Ibaragi, Soichiro; Isowa, Sachiko; Kishimoto, Koji; Mese, Hiroshi; Nishiyama, Akiyoshi; Sasaki, Akira.

In: Journal of Cell Communication and Signaling, Vol. 1, No. 2, 2007, p. 103-111.

Research output: Contribution to journalArticle

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AB - Osteosarcoma is the most common primary malignant bone tumor, accounting for approximately 20% of all primary sarcomas in bone. Although treatment modalities have been improved over the past decades, it is still a tumor with a high mortality rate in children and young adults. Based on histological considerations, osteo-sarcoma arises from impaired differentiation of these immature cells into more mature types and that correction of this impairment may reduce malignancy and increase the efficiency of chemotherapy. The purpose of this study was to determine the effect of specific inhibitors of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK) and p38 on the differentiation of human osteosar-coma cell line SaOS-2 cells. We found that PD98059, a specific inhibitor of MEK, inhibited the serum-stimulated proliferation of SaOS-2 cells; whereas SB203580, a specific inhibitor of p38 MAPK, had little effect on it. SB203580 suppressed ALPase activity, gene expression of type I collagen, and expression of ALP and BMP-2 mRNAs; whereas PD98059 upregulated them dose depen-dently. In addition, immunoblot and immunostaining analysis revealed that phosphorylation of ERK was increased by treatment with SB203580; whereas PD98059 increased the phosphorylation of p38, which implies a seesaw-like balance between ERK and p38 phosphoryla-tion. We suggest that osteosarcoma cell differentiation is regulated by the balance between the activities of the ERK and p38 pathways and that the MEK/ERK pathway negatively regulates osteosarcoma cell differentiation, whereas the p38 pathway does so positively. MEK inhibitor may thus be a good candidate for altering the expression of the osteosarcoma malignant phenotype.

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