標題: Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad
作者: Chang, Shun-Fu
Chang, Cheng Allen
Lee, Ding-Yu
Leet, Pei-Ling
Yeh, Yu-Ming
Yeh, Chiuan-Ren
Cheng, Cheng-Kung
Chien, Shu
Chiu, Jeng-Jiann
生物科技學系
Department of Biological Science and Technology
關鍵字: mechanical force;BMP;differentiation;Runx2
公開日期: 11-Mar-2008
摘要: 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 G(0)/G(1) arrest; in contrast, shear stress (12 dyneS/cm(2)) induced G(2)/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 11311 and p21(CIP1) and decreased expressions of cyclins A, D1, and E, cyclin-dependent protein kinases (Cdk)-1, -2, -4, and -6, and p27(KIP1) 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 alpha(v)beta(3) and beta(1), 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 alpha(v)beta(3) and beta(1), integrins through Smad5. Our findings provide insights into the mechanism by which shear stress induces G(2)/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.
URI: http://dx.doi.org/10.1073/pnas.0712353105
http://hdl.handle.net/11536/9578
ISSN: 0027-8424
DOI: 10.1073/pnas.0712353105
期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume: 105
Issue: 10
起始頁: 3927
結束頁: 3932
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