Killing tumor cells through their surface beta(2)-microglobulin or major histocompatibility complex class I molecules.
Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for beta(2)-microglobulin (beta(2)M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against beta(2)M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-gamma2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although beta(2)M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting beta(2)M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for beta(2)M/MHC class I-expressing malignancies. Cancer 2010. (c) 2010 American Cancer Society.
Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Jing
J
Yang
Qing
Q
Yi
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D019337:Hematologic Neoplasms / Q000188:drug therapy; D015395:Histocompatibility Antigens Class I; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction; D001613:beta 2-Microglobulin
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin