Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad

Shun Fu Chang, Cheng Allen Chang, Ding Yu Lee, Pei Ling Lee, Yu Ming Yeh, Chiuan Ren Yeh, Kung Cheng, Shu Chien, Jeng Jiann Chiu

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating cell cycle distribution in four tumor cell lines and the underlying mechanisms. In all four cell lines, incubation under static conditions for 24 or 48 h led to G0/G 1 arrest; in contrast, shear stress (12 dynes/cm2) induced G2/M arrest. The molecular basis of the shear effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 osteosarcoma cells. Shear stress induced increased expressions of cyclin B1 and p21CIP1 and decreased expressions of cyclins A, D1, and E, cyclin-dependent protein kinases (Cdk)-1, -2, -4, and -6, and p27KIP1 as well as a decrease in Cdk1 activity. Using specific antibodies and small interfering RNA, we found that the shear-induced G2/M arrest and corresponding changes in G2/M regulatory protein expression and activity were mediated by αvβ3 and β1 integrins through bone morphogenetic protein receptor type IA-specific Smad1 and Smad5. Shear stress also down-regulated runt-related transcription factor 2 (Runx2) binding activity and osteocalcin and alkaline phosphatase expressions in MG63 cells; these responses were mediated by αvβ3 and β1 integrins through Smad5. Our findings provide insights into the mechanism by which shear stress induces G2/M arrest in tumor cells and inhibits cell differentiation and demonstrate the importance of mechanical microenvironment in modulating molecular signaling, gene expression, cell cycle, and functions in tumor cells.

Original languageEnglish
Pages (from-to)3927-3932
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number10
DOIs
Publication statusPublished - Mar 25 2008
Externally publishedYes

Keywords

  • BMP
  • Differentiation
  • Mechanical force
  • Runx2

ASJC Scopus subject areas

  • General

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