title: Inhibition of β2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. Sajni.Josson@cshs.org
authors.forename: Sajni
authors.initials: S
authors.lastname: Josson
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Murali
authors.initials: M
authors.lastname: Gururajan
authors.forename: Takeo
authors.initials: T
authors.lastname: Nomura
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Yang
authors.forename: Jin-Tai
authors.initials: JT
authors.lastname: Lin
authors.forename: Roger
authors.initials: R
authors.lastname: Bridgman
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Chu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Johnstone
authors.forename: Majd
authors.initials: M
authors.lastname: Zayzafoon
authors.forename: Peizhen
authors.initials: P
authors.lastname: Hu
authors.forename: Haiyen
authors.initials: H
authors.lastname: Zhau
authors.forename: Dror
authors.initials: D
authors.lastname: Berel
authors.forename: Andre
authors.initials: A
authors.lastname: Rogatko
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000276:immunology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D001613:beta 2-Microglobulin / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011838:Radiation-Sensitizing Agents; D001613:beta 2-Microglobulin; D007501:Iron