Inhibition of β2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells

• Published in: PloS one Vol. 8; no. 7; p. e68366
• Main Authors: Josson, Sajni, Matsuoka, Yasuhiro, Gururajan, Murali, Nomura, Takeo, Huang, Wen-Chin, Yang, Xiaojian, Lin, Jin-Tai, Bridgman, Roger, Chu, Chia-Yi, Johnstone, Peter A, Zayzafoon, Majd, Hu, Peizhen, Zhau, Haiyen, Berel, Dror, Rogatko, Andre, Chung, Leland W K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-07-2013; Public Library of Science (PLoS)
• Subjects: Androgens; Animal models; Animals; Antibodies - pharmacology; Antibodies - therapeutic use; beta 2-Microglobulin - antagonists & inhibitors; beta 2-Microglobulin - immunology; beta 2-Microglobulin - metabolism; Bioinformatics; Biology; Bone cancer; Bone growth; Breast cancer; Cancer; Chemical compounds; Chemotherapy; Clonal deletion; Combined Modality Therapy; Deoxyribonucleic acid; DNA; DNA repair; Hemochromatosis; Hemochromatosis Protein; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Humans; In vivo methods and tests; Inhibition; Iron; Iron - metabolism; Iron Overload - chemically induced; Iron Overload - metabolism; Kidney cancer; Kidneys; Kinases; Lung cancer; Male; Medicine; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - immunology; Membrane Proteins - metabolism; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - immunology; Oncology; Oxygen; Pharmacology; Physicians; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Proteins; Radiation; Radiation Tolerance - drug effects; Radiation Tolerance - genetics; Radiation-Sensitizing Agents - pharmacology; Radiation-Sensitizing Agents - therapeutic use; Reactive oxygen species; Reagents; Repair; Sensitivity; Sensitivity enhancement; Studies; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts; Los Angeles California; California; Alabama; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068366

Bone metastasis is the most lethal form of several cancers. The β2-microglobulin (β2-M)/hemochromatosis (HFE) complex plays an important role in cancer development and bone metastasis. We demonstrated previously that overexpression of β2-M in prostate, breast, lung and renal cancer leads to increased bone metastasis in mouse models. Therefore, we hypothesized that β2-M is a rational target to treat prostate cancer bone metastasis.
In this study, we demonstrate the role of β2-M and its binding partner, HFE, in modulating radiation sensitivity and chemo-sensitivity of prostate cancer. By genetic deletion of β2-M or HFE or using an anti-β2-M antibody (Ab), we demonstrate that prostate cancer cells are sensitive to radiation in vitro and in vivo. Inhibition of β2-M or HFE sensitized prostate cancer cells to radiation by increasing iron and reactive oxygen species and decreasing DNA repair and stress response proteins. Using xenograft mouse model, we demonstrate that anti-β2-M Ab sensitizes prostate cancer cells to radiation treatment. Additionally, anti-β2-M Ab was able to prevent tumor growth in an immunocompetent spontaneous prostate cancer mouse model. Since bone metastasis is lethal, we used a bone xenograft model to test the ability of anti-β2-M Ab and radiation to block tumor growth in the bone. Combination treatment significantly prevented tumor growth in the bone xenograft model by inhibiting β2-M and inducing iron overload. In addition to radiation sensitive effects, inhibition of β2-M sensitized prostate cancer cells to chemotherapeutic agents.
Since prostate cancer bone metastatic patients have high β2-M in the tumor tissue and in the secreted form, targeting β2-M with anti-β2-M Ab is a promising therapeutic agent. Additionally, inhibition of β2-M sensitizes cancer cells to clinically used therapies such as radiation by inducing iron overload and decreasing DNA repair enzymes.