title: Osteoactivin (GPNMB) ectodomain protein promotes growth and invasive behavior of human lung cancer cells.
abstract: The potential application of GPNMB/OA as a therapeutic target for lung cancer will require a greater understanding of the impact of GPNMB/OA ectodomain (ECD) protein shedding into tumor tissues. Thus, in this work we characterized GPNMB/OA expression and extent of shedding of its ECD protein while evaluating the impact on lung cancer progression using three non-small cell lung cancer (NSCLC) cell lines: A549, SK-MES-1 and calu-6. We observed a direct correlation (R2 = 0.89) between GPNMB/OA expression on NSCLC cells and the extent of GPNMB/OA ECD protein shedding. Meanwhile, siRNA-mediated knockdown of GPNMB/OA in cancer cells significantly reduced GPNMB/OA ECD protein shedding, migration, invasion and adhesion to extracellular matrix materials. Also, exogenous treatment of cancer cells (expressing low GPNMB/OA) with recombinant GPNMB/OA protein (rOA) significantly facilitated cell invasion and migration, but the effects of rOA was negated by inclusion of a selective RGD peptide. Further studies in athymic (nu/nu) mice-bearing calu-6 showed that intratumoral supplementation with rOA effectively facilitated in vivo tumor growth as characterized by a high number of proliferating cells (Ki67 staining) coupled with a low number of apoptotic cells. Taken together, our results accentuate the relevance of GPNMB/OA ECD protein shedding to progression of lung cancer. Thus, strategies that suppress GPNMB/OA expression on lung cancer cells as well as negate shedding of GPNMB/OA ECD protein are worthy of consideration in lung cancer therapeutics.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.|School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA.
authors.forename: Moses O
authors.initials: MO
authors.lastname: Oyewumi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.|School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA.
authors.forename: Dharani
authors.initials: D
authors.lastname: Manickavasagam
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.|Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Novak
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wehrung
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Nikola
authors.initials: N
authors.lastname: Paulic
authors.affiliation: School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA.|Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Fouad M
authors.initials: FM
authors.lastname: Moussa
authors.affiliation: School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA.|Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Sondag
authors.affiliation: School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA.|Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Fayez F
authors.initials: FF
authors.lastname: Safadi
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D000072417:Protein Domains; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C503042:GPNMB protein, human; D008562:Membrane Glycoproteins
keywords: GPNMB; NSCLC; cell adhesion; integrin; lung cancer