Integrin alphavbeta3-mediated transcriptional regulation of TIMP-1 in a human ovarian cancer cell line.
We have previously reported that a disintegrin inhibits solid tumor growth and metastasis in mouse model [I.C. Kang, Y.D. Lee, D.S. Kim, A novel disintegrin salmosin inhibits tumor angiogenesis, Cancer Res. 59 (1999) 3754-3760; S.I. Kim, K.S. Kim, H.S. Kim, D.S. Kim, Y. Jang, K.H. Chung, Y.S. Park, Inhibitory effect of the salmosin gene transferred by cationic liposomes on the progression of B16BL6 tumors, Cancer Res. 63 (2003) 6458-462]. In this study, we have investigated the modulatory effect of a disintegrin, saxatilin, on the balance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in human ovarian cancer cell line MDAH 2774. Functional mechanism of the disintegrin-mediated transcriptional regulation of MMP-9 and TIMP-1 was examined in the ovarian cancer cell line. Saxatilin strongly induced TIMP-1 expression in dose- and time-dependent manners, while the disintegrin suppressed MMP-9 expression. Further analyses clearly indicated that interaction of the disintegrin and integrin alphavbeta3 results in the TIMP-1 promoter activation via c-fos to suppress TNF-alpha-induced cancer cell invasion. These results demonstrate that integrin alphavbeta3-mediated transcriptional regulation of MMP-9 and TIMP-1 is critical for suppressing the ovarian cancer cell invasion.
National Research Laboratory, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
Dong Seok
DS
Kim
National Research Laboratory, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
Ok-Hee
OH
Jeon
National Research Laboratory, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
Hee Doo
HD
Lee
Division of Life Sciences, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Kyung Ho
KH
Yoo
National Research Laboratory, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea. Electronic address: dskim@yonsei.ac.kr.
Doo-Sik
DS
Kim
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D019483:Disintegrins / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000819:agonists / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D019483:Disintegrins; D039302:Integrin alphaVbeta3; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; C459080:saxatilin; D020780:Matrix Metalloproteinase 9