Syndecan-2 affects the basal and chemotherapy-induced apoptosis in osteosarcoma.
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.
Orosco
Armelle
A
INSERM U606 and Université Paris 7, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris cedex 10, France.
Fromigué
Olivia
O
Bazille
Céline
C
Entz-Werle
Natacha
N
Levillain
Pierre
P
Marie
Pierre J
PJ
Modrowski
Dominique
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008727:Methotrexate / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053669:Syndecan-2 / Q000096:biosynthesis* / Q000235:genetics
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D053669:Syndecan-2; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate