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. 2013 Jul 10;8(7):e68366.
doi: 10.1371/journal.pone.0068366. Print 2013.

Inhibition of β2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells (V体育ios版)

Sajni Josson  1 , Yasuhiro Matsuoka, Murali Gururajan, Takeo Nomura, Wen-Chin Huang, Xiaojian Yang, Jin-Tai Lin, Roger Bridgman, Chia-Yi Chu, Peter A Johnstone, Majd Zayzafoon, Peizhen Hu, Haiyen Zhau, Dror Berel, Andre Rogatko, Leland W K Chung
Affiliations

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

Sajni Josson et al. PLoS One. .

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 VSports手机版. .

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 V体育安卓版. 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. .

Conclusion: 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 V体育ios版. Additionally, inhibition of β2-M sensitizes cancer cells to clinically used therapies such as radiation by inducing iron overload and decreasing DNA repair enzymes. .

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Figure 1. Anti-β2-M Ab sensitizes prostate cancer cells to radiation in vivo.
A. Radiation sensitivity of ARCaPE and ARCaPM prostate cancer cells by clongenic assay. (** p<0.01, *** p<0.001, Student’s t test). B. ARCaPM cells are sensitized to radiation in the presence of anti-β2-M Ab using clongenic assay. (*p<0.03, *** p<0.008, ANOVA). C. Effect of anti-β2-M Ab (0.8 mg/kg) and radiation (15 Gy) on tumor growth in subcutaneous ARCaPM xenograft nude mice model. (** p<0.01, Student’s t test).
Figure 2
Figure 2. Anti-β2-M Ab increases iron and decreases DNA repair enzymes in prostate cancer cells.
A. Iron staining in control and anti-β2-M Ab (5 µg/ml) treated cells using iron staining kit in ARCaPM prostate cancer cell lines. B. Mitochondrial superoxide levels in response to anti-β2-M Ab treatment in a time and dose dependent manner in i. ARCaPM, ii. ARCaPE prostate cancer cell lines (***p<0.001, Student’s t test) and iii. p69 immortalized prostate epithelial cells using MitoSOX dye. C. Mitochondrial superoxide in ARCaPM, KDHFE1 and KDHFE3 using MitoSOX dye (*p<0.05, Student’s t test). D. Expression of stress response proteins and DNA repair enzymes in C4-2B Neo control and β2-M knockdown cell lines. i.β2-M protein expression, ii. HSP27 and HSP70 protein expression and iii. NUDT1 and MPG protein expression. NUDT1 and MPG protein expression in response to anti- β2-M Ab treatment in LNCaP and C4-2 prostate cancer cells.
Figure 3
Figure 3. Anti-β2-M Ab prevents tumor formation in spontaneous prostate cancer TRAMP mouse model.
A. Cell viability of TRAMP C1 and TRAMP C2 prostate cancer cells in response to anti-β2-M Ab. (***p<0.001, Student’s t test). B. Merged near infra-red and X-ray image of abdomen of TRAMP mice treated with control IgG and anti-β2-M Ab (n = 4). Representative parental mice used as additional control (C57BL/6 mice). The tumorigenecity of control IgG antibody group was 100% (n = 4) and the tumorigenecity of anti-β2-M Ab treated group was 25% (n = 4). C. H&E images of prostates of control IgG mice and anti-β2-M Ab treated mice (10X). D. Immune cell (T and B cells) numbers of wild type mice, control IgG mice and anti-β2-M Ab treated mice measured by flow cytometry. E. Body weights of TRAMP mice treated with IgG or anti-β2-M Ab.
Figure 4
Figure 4. Combination treatment of anti-β2-M Ab and radiation in intra-tibial mouse model of prostate cancer.
Tumor incidence in mice tibias were analyzed from H&E images and x-ray scans. The tumorigenecity of control group was 94% (n = 18 tibias) and the tumorigenecity of anti-β2-M Ab+irradiation (IR) treated group was 67% (n = 18 tibias). A. Tumor progression in control and combination treatment (anti-β2-M Ab and irradiation) analyzed by PSA measurements (ng/ml). (***p<0.006, Student’s t test). B. Immunohistochemical staining of tibias in control and combination treatment group stained for H&E, β2-M protein, iron staining, p-CREB and p-histone H3 (10X).
Figure 5
Figure 5. Anti-β2-M Ab sensitizes prostate cancer cells to chemotherapeutic cancer drugs.
A. Cell viability of C4-2B Neo control cells and KDβ2-M cells in response to: taxotere (0.3 µM), cisplatin (10 µM) and PS341 (1 µM). (***p<0.001, Student’s t test) B. Cell viability of DU154 prostate cancer cells in response to combination of anti-β2-M Ab (0.5 µg/ml) and cisplatin (100 µM)/doxorubicin (100 µM). (***p<0.001, Student’s t test). C. Cell viability of PC-3 prostate cancer cells in response to combination of anti-β2-M Ab (1 µg/ml) and cisplatin (100 µM). (***p<0.001, Student’s t test).
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