The C‐terminal domain of focal adhesion kinase reduces the tumor cell invasiveness in chondrosarcoma cell lines

Journal of Orthopaedic Research - Tập 21 - Trang 1071-1080 - 2003
Jin Woo Lee1, Yun Hee Kim1, Hee Boong Park2, Li-Hui Xu2, William G Cance2, Joel A Block3, Sean P Scully4
1Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, South Korea
2Department of Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
3Department of Rheumatology and Biochemistry, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL, USA
4Orthopedic Research, Mayo Clinic, 200 First Street SW Rochester, MN 55905, USA

Tóm tắt

AbstractHuman chondrosarcoma is a malignancy that has no effective systemic therapy, making the interruption of the metastatic cascade critical to enhance patient survival. The processes of local invasion and metastases share similar mechanisms at a cellular level. Focal adhesion kinase (FAK) has been implicated in local invasion of malignant tumor cells. In the current manuscript we examine the effect of FAK inhibition on cell attachment to extracellular matrix (ECM) and in vitro invasion. Bovine articular chondrocytes and two human chondrosarcoma cell lines were utilized to examine FAK activity in tumor cell invasiveness. Endogenous FAK activity was inhibited by adenoviral transfection with the C‐terminal domain of FAK. This inhibition resulted from decreased FAK phosphorylation, while FAK expression remained unchanged. Inhibition of FAK phosphorylation and hence its activity lead to decreased cell adhesion to Type II collagen and decreased cell invasiveness. These effects were not due to changes in integrin expression, indicating that the inhibition was the result of disruption of outside: in signaling. There are three important aspects to these results. The first is that interruption of transmembrane signaling can affect cell attachment. The second is that in chondrosarcoma, cell differentiation correlates with FAK expression and metastatic potential. Thirdly, that cell invasiveness correlates with FAK activity and implies a mechanistic role for this molecular complex in local invasion and metastasis. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.

Tài liệu tham khảo

10.1128/MCB.13.8.4648 10.3109/03008209109152446 10.2106/00004623-199173050-00002 Block JA, 1992, Heterogeneity of keratan sulfate substituted on human chondrocytic large proteoglycans, J Biol Chem, 267, 7245, 10.1016/S0021-9258(18)42511-2 10.1038/sj.neo.7900149 10.1083/jcb.119.4.893 Cance WG, 1994, Rak, a novel nuclear tyrosine kinase expressed in epithelial cells, Cell Growth Differ, 5, 1347 Cance WG, 2000, Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: Correlation with preinvasive and invasive phenotypes, Clin Cancer Res, 6, 2417 10.2741/Cary 10.1126/science.7716514 10.1016/S0955-0674(96)80107-4 Giancotti FG, 1994, Integrin‐mediated adhesion and signaling in tumorigenesis, Biochim Biophys Acta, 1198, 47 10.1091/mbc.2.11.951 10.1073/pnas.89.18.8487 10.1002/bies.950190208 10.1016/0046-8177(95)90004-7 10.1242/jcs.110.4.401 10.1038/377539a0 10.1016/0304-3835(96)04273-5 10.1016/0304-3835(96)04274-7 10.1007/BF01200722 10.1083/jcb.140.4.961 10.1002/(SICI)1097-0347(199812)20:8<745::AID-HED14>3.0.CO;2-Z 10.1016/0022-1759(84)90477-0 10.1016/S0736-0266(01)00073-0 Lewis MM, 1987, Benign and malignant cartilage tumors, Instr Course Lect, 36, 87 10.3109/07357909109018952 MillerDR MankinHJ. A comparison of collagen synthesis by different categories of human chondrosarcoma in organ culture.Clin Orthop1982;252–7. 10.1016/S0074-7696(08)61347-9 Owens LV, 1995, Overexpression of the focal adhesion kinase (p125fak) in invasive human tumors, Cancer Res, 55, 2752 10.1007/BF01221195 Prevec L, 1991, Immune response to HIV‐I gag antigens induced by recombinant adenovirus vectors in mice and rhesus macaque monkeys, J Acquir Immune Defic Syndr, 4, 568 10.1128/MCB.17.12.6906 10.1038/380538a0 10.1016/S0065-230X(08)60772-1 10.1159/000217975 10.1172/JCI114957 10.1146/annurev.cellbio.12.1.697 10.1073/pnas.89.11.5192 10.1146/annurev.cb.11.110195.003001 10.1002/jor.1100160406 ScullySP BerendKR TothA et al. Interstitial collagenase gene expression correlates with in vitro invasion in human chondrosarcoma.Clin Orthop2000;291–303. Springfield DS, 1996, Chondrosarcoma: A review, Instr Course Lect, 45, 417 Symington BE, 1992, Fibronectin receptor modulates cyclin‐dependent kinase activity, J Biol Chem, 267, 25744, 10.1016/S0021-9258(18)35671-0 10.1007/BF01605779 10.1016/0140-6736(93)92881-S 10.1002/(SICI)1097-0142(19971015)80:8 <1529::AID-CNCR2>3.0.CO;2-F 10.1074/jbc.M910027199 Xu LH, 1998, The COOH‐terminal domain of the focal adhesion kinase induces loss of adhesion and cell death in human tumor cells, Cell Growth Differ, 9, 999
Thông tin
Thông tin xuất bản

Journal of Orthopaedic Research

Tập 21

1071-1080

Thông tin tác giả