CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling.
Oncotarget, 2016/11/29;7(48):79925-79942.
Manara MC[1], Terracciano M[1, 2], Mancarella C[1], Sciandra M[1, 3], Guerzoni C[1, 3], Pasello M[1, 3], Grilli A[1], Zini N[4, 5], Picci P[1, 3], Colombo MP[6], Morrione A[2], Scotlandi K[1, 3]
Affiliations
PMID: 27835596DOI: 10.18632/oncotarget.13160
Abstract
CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.
Keywords: CD99; Ewing sarcoma; RAS; antibody; cell death
MeSH terms
12E7 Antigen; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Apoptosis; Bone Neoplasms; Cell Death; Cells, Cultured; Genes, ras; HEK293 Cells; Humans; Pinocytosis; Proteolysis; Receptor, IGF Type 1; Receptors, Somatomedin; Sarcoma, Ewing; Signal Transduction; rac1 GTP-Binding Protein
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