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(American Journal of Pathology. 1998;153:1937-1945.)
© 1998 American Society for Investigative Pathology

Regular Articles

Engagement of CD99 Induces Apoptosis Through a Calcineurin-Independent Pathway in Ewing's Sarcoma Cells

Hae Won Sohn* , Eun Young Choi*{dagger} , Soon Ha Kim* , Im-soon Lee*{dagger} , Doo Hyun Chung* , Uhn A Sung* , Duck Ho Hwang{ddagger} , Sa Sun Cho{ddagger} , Byung Hoon Jun§ , Ja June Jang* , Je Geun Chi* and Seong Hoe Park*{dagger}

From the Departments of Pathology* and Anatomy,{ddagger} Seoul National University College of Medicine, and Institute of Allergy and Clinical Immunology,{dagger} Seoul, and the Department of Otolaryngology,§ Inje University College of Medicine, Kimhae, Korea

Programmed cell death (PCD) is a prominent feature of the development of the immune and nervous systems. In both systems, widespread PCD occurs in primitive progenitor cells during development. In this study, we demonstrated that Ewing's sarcoma (ES) cells, undifferentiated neural precursors, underwent apoptosis upon engagement of CD99 with anti-CD99 monoclonal antibody. Apoptosis via CD99 occurred only in the undifferentiated state of ES cells, but not in differentiated ES cells. CD99-induced apoptosis in ES cells appeared to require de novo synthesis of RNA and protein as well as caspase activation. Cyclosporin A, known to be a potent inhibitor of both calcineurin activation and mitochondrial permeability transition pore opening, inhibited CD99-mediated apoptosis, whereas FK-506, a specific calcineurin inhibitor, did not, indicating the induction of CD99-mediated apoptosis through a calcineurin-independent pathway. Furthermore, the dying cells displayed the reduction of mitochondrial transmembrane potential ({Delta}{Psi}m). These results suggest that CD99 engagement induce CsA-inhibitable mitochondrial permeability transition pore opening, followed by a reduction of {Delta}{Psi}m and caspase activation, thereby leading to apoptosis. Based on these results, we suggest the possible involvement of CD99 in the apoptotic processes that occur during nervous system development and also its application in immunotherapeutic trials for ES cases.




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