β2-Microglobulin-mediated signaling as a target for cancer therapy

• Published in: Anti-cancer agents in medicinal chemistry Vol. 14; no. 3; p. 343
• Main Authors: Nomura, Takeo, Huang, Wen-Chin, Zhau, Haiyen E, Josson, Sajni, Mimata, Hiromitsu, Chung, Leland W K
• Format: Journal Article
• Language: English
• Published: Netherlands 01.03.2014
• Subjects: Animals; Antibodies - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; beta 2-Microglobulin - immunology; beta 2-Microglobulin - metabolism; Biomarkers, Tumor - metabolism; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Bone Neoplasms - secondary; Epithelial-Mesenchymal Transition; Genes, MHC Class I; Humans; Mesenchymal Stromal Cells - metabolism; Molecular Targeted Therapy; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Signal Transduction; Tumor Cells, Cultured
• ISSN: 1875-5992
• DOI: 10.2174/18715206113139990092

β2-microglobulin (β2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. β2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, β2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that β2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that β2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against β2-m have remarkable tumoricidal activity in cancer, through β2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, β-catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of β2-m and β2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding β2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers.