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Syndecan-2 Affects the Basal and Chemotherapy-Induced Apoptosis in Osteosarcoma

¹ Inserm, U606 and ² Université Paris 7, Paris, France; ³ Biochemistry and Molecular Biology Department, CHRU Hautepierre, Strasbourg, France; and ⁴ Department of Anatomy and Pathologic Cytology, Medical University of Poitiers, Poitiers, France

Requests for reprints: Dominique Modrowski, Unit 606, Institut National de la Sante et de la Recherche Medicale, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 cedex 10, Paris, France. Phone: 33-1-49-95-63-58; Fax: 33-1-49-95-84-52; E-mail: dominique.modrowski{at}larib.inserm.fr.

Syndecans are transmembrane heparan sulfate proteoglycans controlling cell adhesion, migration, and proliferation. We previously showed that syndecan-2 is involved in the control of apoptosis in cultured osteosarcoma cells. These data led us to the hypothesis that syndecan-2 may play a role in the apoptotic signaling in bone tumors. We immunohistochemically analyzed tissue sections from biopsies from 21 patients with well-characterized osteosarcoma. These tissues expressed low levels of syndecan-2 compared with osteoblasts and osteocytes in normal bone. Cultured human osteosarcoma cells also produced lower mRNA levels of syndecan-2 than normal osteoblastic cells. Moreover, the presence of syndecan-2 correlated with spontaneous apoptosis in osteosarcoma tissues as assessed by detection of DNA fragmentation in situ. Overexpression of syndecan-2 resulted in decreased number of migrating and invading U2OS osteosarcoma cells in Matrigel. In addition, overexpression of syndecan-2 sensitized human osteosarcoma cells to chemotherapy-induced apoptosis, increasing the response to methotrexate, doxorubicin, and cisplatin. Consistently, knockdown of the proteoglycan using stable transfection with a plasmid coding small interfering RNA resulted in inhibition of chemotherapy-induced apoptosis. Analysis of syndecan-2 expression both in biopsies and in corresponding postchemotherapy-resected tumors, as well as in cells treated with methotrexate or doxorubicin, showed that the cytotoxic action of chemotherapy can be associated with an increase in syndecan-2. These results provide support for a tumor-suppressor function for syndecan-2 and suggest that dysregulation of apoptosis may be related to abnormal syndecan-2 expression or induction in osteosarcoma. Moreover, our data identify syndecan-2 as a new factor mediating the antioncogenic effect of chemotherapeutic drugs. [Cancer Res 2007;67(8):3708–14]

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