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PC Cell–Derived Growth Factor Confers Resistance to Dexamethasone and Promotes Tumorigenesis in Human Multiple Myeloma

Authors' Affiliations: ¹ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy; ² Program in Oncology, Marlene and Stewart Greenebaum Cancer Center of the University of Maryland, Baltimore, Maryland; and ³ Research and Development Department, A&G Pharmaceutical, Inc., Columbia, Maryland

Requests for reprints: Ginette Serrero, A&G Pharmaceutical, Inc., 9130 Red Branch Road, Suite U, Columbia MD 21045. Phone: 410-884-4100; Fax: 410-884-1607; E-mail: gserrero{at}agrx.net.

Purpose: We have shown previously that the 88 kDa glycoprotein PC cell–derived growth factor (PCDGF/GP88) is expressed and acts as an autocrine growth factor in human multiple myeloma cells. The present study investigates whether PCDGF/GP88 expression in multiple myeloma cells leads to the development of resistance to dexamethasone, a conventional drug for multiple myeloma patients.

Experimental Design: PCDGF functions and signaling pathways in dexamethasone-induced apoptosis were studied using a representative dexamethasone-sensitive multiple myeloma cell line ARP-1. The effect of PCDGF/GP88 was further confirmed in PCDGF/GP88–overexpressed ARP-1 cells.

Results: Dexamethasone inhibits cell growth and induces apoptosis in a time- and dose-dependent fashion. Exogenous addition of PCDGF/GP88 to the ARP-1 cells prevented dexamethasone-induced apoptosis as examined by flow cytometry analysis and poly(ADP-ribose)polymerase cleavage assay. Signaling studies showed that mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and nuclear factor-B were involved in the antiapoptotic effect of PCDGF/GP88. Overexpression of PCDGF/GP88 in ARP-1 cells rendered the cells refractory to dexamethasone-mediated apoptosis, enhanced their ability to form colonies in soft agar, and to form tumors in vivo without any change in glucocorticoid receptor expression and function.

Conclusion: These data suggest that expression of PCDGF/GP88 confers resistance to dexamethasone and increase tumorigenesis of multiple myeloma cells in mouse xenografts. Our data here also raises the possibility of PCDGF/GP88 as a potential therapeutic target for dexamethasone-resistant multiple myeloma.

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