title: Membrane type 1 matrix metalloprotease cleaves laminin-10 and promotes prostate cancer cell migration.
abstract: Disruption of the extracellular matrix by proteases is crucial for tumor invasion. Laminin-10 (Ln-10) has previously been identified as a substrate for cell migration and cell adhesion, and is present in the basal lamina (BL) of both normal prostate and prostate cancer. Here, we investigate a role for membrane type 1 matrix metalloprotease (MT1-MMP) in modifying this Ln-10-rich BL. MT1-MMP is a transmembrane member of the MMP family that has been demonstrated to be upregulated as prostate cancer progresses from normal to prostate intraepithelial neoplasia to invasive cancer, suggesting a role for MT1-MMP in the invasion of prostate cancer. We show that MT1-MMP cleaves the alpha5 chain of purified human Ln-10 from its 350-kDa form into 310-, 190-, 160-, and 45-kDa fragments. This cleavage causes a decrease in DU-145 prostate cancer cell adhesion to purified Ln-10, and an increase in transmigration of DU-145 cells through cleaved Ln-10. We also show that prostate cancer cells expressing membrane-bound MT1-MMP cleave the alpha5 chain of Ln-10. Ln alpha5-chain cleavage is also observed in human prostate cancer tissues. These findings suggest that prostate cancer cells expressing high levels of MT1-MMP have increased invasive potential through their ability to degrade and invade Ln-10 barriers.
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Elisabeth L
authors.initials: EL
authors.lastname: Bair
authors.forename: Man Ling
authors.initials: ML
authors.lastname: Chen
authors.forename: Kathy
authors.initials: K
authors.lastname: McDaniel
authors.forename: Kiyotoshi
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cress
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Nagle
authors.forename: George Timothy
authors.initials: GT
authors.lastname: Bowden
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D008957:Models, Genetic; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D007797:Laminin; C119013:laminin 10; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases