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.
Kim
Dong Seok
DS
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.
Jeon
Ok-Hee
OH
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.
Lee
Hee Doo
HD
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.
Yoo
Kyung Ho
KH
Division of Life Sciences, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Kim
Doo-Sik
DS
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.
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