Osteoactivin (GPNMB) ectodomain protein promotes growth and invasive behavior of human lung cancer cells

// Moses O. Oyewumi 1, 2 , Dharani Manickavasagam 1, 2 , Kimberly Novak 1, 3 , Daniel Wehrung 1 , Nikola Paulic 1 , Fouad M. Moussa 2, 3 , Gregory R. Sondag 2, 3 , Fayez F. Safadi 2, 3 1 Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA 2 School of Biomedical Sciences, Kent State University, Kent, OH 44240, USA 3 Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA Correspondence to: Moses O. Oyewumi, e-mail: moyewumi@neomed.edu Keywords: GPNMB, cell adhesion, NSCLC, integrin, lung cancer Received: September 08, 2015      Accepted: January 23, 2016      Published: February 11, 2016 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 ( R 2 = 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.