| First Author | Josson S | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 7 | Pages | e68366 |
| PubMed ID | 23874600 | Mgi Jnum | J:204407 |
| Mgi Id | MGI:5532458 | Doi | 10.1371/journal.pone.0068366 |
| Citation | Josson S, et al. (2013) Inhibition of beta2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells. PLoS One 8(7):e68366 |
| abstractText | BACKGROUND: Bone metastasis is the most lethal form of several cancers. The beta2-microglobulin (beta2-M)/hemochromatosis (HFE) complex plays an important role in cancer development and bone metastasis. We demonstrated previously that overexpression of beta2-M in prostate, breast, lung and renal cancer leads to increased bone metastasis in mouse models. Therefore, we hypothesized that beta2-M is a rational target to treat prostate cancer bone metastasis. RESULTS: In this study, we demonstrate the role of beta2-M and its binding partner, HFE, in modulating radiation sensitivity and chemo-sensitivity of prostate cancer. By genetic deletion of beta2-M or HFE or using an anti-beta2-M antibody (Ab), we demonstrate that prostate cancer cells are sensitive to radiation in vitro and in vivo. Inhibition of beta2-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-beta2-M Ab sensitizes prostate cancer cells to radiation treatment. Additionally, anti-beta2-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-beta2-M Ab and radiation to block tumor growth in the bone. Combination treatment significantly prevented tumor growth in the bone xenograft model by inhibiting beta2-M and inducing iron overload. In addition to radiation sensitive effects, inhibition of beta2-M sensitized prostate cancer cells to chemotherapeutic agents. CONCLUSION: Since prostate cancer bone metastatic patients have high beta2-M in the tumor tissue and in the secreted form, targeting beta2-M with anti-beta2-M Ab is a promising therapeutic agent. Additionally, inhibition of beta2-M sensitizes cancer cells to clinically used therapies such as radiation by inducing iron overload and decreasing DNA repair enzymes. |
