Activation of pro-gelatinase B by endometase/matrilysin-2 promotes invasion of human prostate cancer cells.
This work has explored a putative biochemical mechanism by which endometase/matrilysin-2/matrix metalloproteinase-26 (MMP-26) may promote human prostate cancer cell invasion. Here, we showed that the levels of MMP-26 protein in human prostate carcinomas from multiple patients were significantly higher than those in prostatitis, benign prostate hyperplasia, and normal prostate glandular tissues. The role of MMP-26 in prostate cancer progression is unknown. MMP-26 was capable of activating pro-MMP-9 by cleavage at the Ala(93)-Met(94) site of the prepro-enzyme. This activation proceeded in a time- and dose-dependent manner, facilitating the efficient cleavage of fibronectin by MMP-9. The activated MMP-9 products generated by MMP-26 appeared more stable than those cleaved by MMP-7 under the conditions tested. To investigate the contribution of MMP-26 to cancer cell invasion via the activation of MMP-9, highly invasive and metastatic human prostate carcinoma cells, androgen-repressed prostate cancer (ARCaP) cells were selected as a working model. ARCaP cells express both MMP-26 and MMP-9. Specific anti-MMP-26 and anti-MMP-9 functional blocking antibodies both reduced the invasiveness of ARCaP cells across fibronectin or type IV collagen. Furthermore, the introduction of MMP-26 antisense cDNA into ARCaP cells significantly reduced the MMP-26 protein level in these cells and strongly suppressed the invasiveness of ARCaP cells. Double immunofluorescence staining and confocal laser scanning microscopic images revealed that MMP-26 and MMP-9 were co-localized in parental and MMP-26 sense-transfected ARCaP cells. Moreover, MMP-26 and MMP-9 proteins were both expressed in the same human prostate carcinoma tissue samples examined. These results indicate that MMP-26 may be a physiological and pathological activator of pro-MMP-9.
Zhao
Yun-Ge
YG
Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306-4390, USA.
Xiao
Ai-Zhen
AZ
Newcomer
Robert G
RG
Park
Hyun I
HI
Kang
Tiebang
T
Chung
Leland W K
LW
Swanson
Mark G
MG
Zhau
Haiyen E
HE
Kurhanewicz
John
J
Sang
Qing-Xiang Amy
QX
D002465:Cell Movement / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D014407:Tumor Cells, Cultured
D024141:Collagen Type IV; D004792:Enzyme Precursors; D005353:Fibronectins; D020319:Oligodeoxyribonucleotides, Antisense; D018093:Gelatinases; C410599:MMP26 protein, human; D020782:Matrix Metalloproteinases; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases; C069860:progelatinase