Inhibitor of DASH proteases affects expression of adhesion molecules in osteoclasts and reduces myeloma growth and bone disease.
Dipeptidyl peptidase (DPP) IV activity and/or structure homologues (DASH) are serine proteases implicated in tumourigenesis. We previously found that a DASH protease, fibroblast activation protein (FAP), was involved in osteoclast-induced myeloma growth. Here we further demonstrated expression of various adhesion molecules in osteoclasts cultured alone or cocultured with myeloma cells, and tested the effects of DASH inhibitor, PT-100, on myeloma cell growth, bone disease, osteoclast differentiation and activity, and expression of adhesion molecules in osteoclasts. PT-100 had no direct effects on viability of myeloma cells or mature osteoclasts, but significantly reduced survival of myeloma cells cocultured with osteoclasts. Real-time PCR array for 85 adhesion molecules revealed upregulation of 17 genes in osteoclasts after coculture with myeloma cells. Treatment of myeloma/osteoclast cocultures with PT-100 significantly downregulated 18 of 85 tested genes in osteoclasts, some of which are known to play roles in tumourigenesis and osteoclastogenesis. PT-100 also inhibited osteoclast differentiation and subsequent pit formation. Resorption activity of mature osteoclasts and differentiation of osteoblasts were not affected by PT-100. In primary myelomatous severe combined immunodeficient (SCID)-hu mice PT-100 reduced osteoclast activity, bone resorption and tumour burden. These data demonstrated that DASH proteases are involved in myeloma bone disease and tumour growth.
Pennisi
Angela
A
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Li
Xin
X
Ling
Wen
W
Khan
Sharmin
S
Gaddy
Dana
D
Suva
Larry J
LJ
Barlogie
Bart
B
Shaughnessy
John D
JD
Aziz
Nazneen
N
Yaccoby
Shmuel
S
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D001897:Boronic Acids / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D004151:Dipeptides / Q000627:therapeutic use*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000097:blood; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D014408:Biomarkers, Tumor; D001897:Boronic Acids; D015815:Cell Adhesion Molecules; D004151:Dipeptides; D007147:Immunoglobulin Light Chains; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; D000469:Alkaline Phosphatase; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C514044:talabostat