Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 β3 chain and induces cell migration

Thirupandiyur S. Udayakumar, Man Ling Chen, Elisabeth L. Bair, Dorothea C. Von Bredow, Anne E. Cress, Raymond B. Nagle, G. Timothy Bowden

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

Degradation of the extracellular matrix by proteolytic enzymes is a central aspect of physiological and pathologic tissue-remodeling processes such as trophoblastic implantation, wound healing, and tumor invasion. We have hypothesized that prostate adenocarcinoma cell invasion through the normal basal lamina is attributable in part to metalloproteinase-induced cleavage of laminin-5 (Ln-5) and enhanced motility of the cancer cells. We studied the role of membrane type-1-matrix metalloproteinase (MT1-MMP) expressed on the surface of prostate tumor cells in cleaving Ln-5 and enhancing the migration of prostate tumor cells. We also determined the nature of the MT1-MMP cleavage of human Ln-5 and how this altered Ln-5 changes the migration of prostate carcinoma cells. We found that human MT1-MMP cleaves purified human Ln-5 to an 80-kDa fragment. Mass spectrometry analyses of the 80-kDa cleaved product by trypsin and chymotrypsin gave 14 and 9 different peptide sequences, respectively, that were identical to the expected amino acid sequence of the Ln-5-β3 chain. The recovered peptides represent 14.4% (trypsin) and 10.3% (chymotrypsin) of Ln-5-β3 chain by amino acid count. Both trypsin and chymotrypsin digestion of MT1-MMP-cleaved product of Ln-5 did not show any other peptides that were identical to the other chains of Ln-5. Using a linear migration assay we found that the Ln-5 cleaved by MT1-MMP enhanced the migration of DU-145 prostate carcinoma cells by 2-fold compared with uncleaved Ln-5. The use of blocked antisense MT1-MMP oligonucleotides inhibited the migration of DU-145 cells on Ln-5. We also found that the prostate carcinoma cells expressing high levels of MT1-MMP, such as PC3N and PPC, demonstrated enhanced migration on human Ln-5-coated substrate, and this migration was inhibited using blocked antisense MT1-MMP oligonucleotides. In conclusion, this is a novel and important finding where we have shown that β3-chain is cleaved by MT1-MMP, and this cleavage enhances migration of prostate cancer cells.

Original languageEnglish (US)
Pages (from-to)2292-2299
Number of pages8
JournalCancer Research
Volume63
Issue number9
StatePublished - May 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Udayakumar, T. S., Chen, M. L., Bair, E. L., Von Bredow, D. C., Cress, A. E., Nagle, R. B., & Bowden, G. T. (2003). Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 β3 chain and induces cell migration. Cancer Research, 63(9), 2292-2299.