Inhibition of β2-Microglobulin/Hemochromatosis Enhances Radiation Sensitivity by Induction of Iron Overload in Prostate Cancer Cells

Abstract

BackgroundBone 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.ResultsIn 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.ConclusionSince 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.

Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis

“…The spread of metastasis may occur via the bloodstream or the lymphatic systems or through both routes [64]. Previous studies have shown that activated β2M is related with the cancer progression of human prostate [12,65], ovarian [17], colon cancer [66], lymphoma and leukemia [67]. β2M controls tumor metastasis and EMT to bone and other soft tissues [14].…”

RANK-mediated signaling network and cancer metastasis

“…β2-m protected against the influx and accumulation of intracellular iron, and lower levels of intracellular iron activated HIF-1α and its target genes including EMT markers and VEGF [31,36]. Knocking down either the HFE protein or β2-m resulted in mesenchymal to epithelial transition (MET), a reversal of EMT, decreased cell proliferation and increased apoptosis in PCa cells [42]. β2-m activates intracellular signaling axes mediated by ERK and sterol regulatory element-binding protein-1 (SREBP-1), that drive lipogenesis and lipid and lipid raft-mediated signaling and could potentially enhance the survival of cancer cells [34].…”

“…β2-m activates intracellular signaling axes mediated by ERK and sterol regulatory element-binding protein-1 (SREBP-1), that drive lipogenesis and lipid and lipid raft-mediated signaling and could potentially enhance the survival of cancer cells [34]. These results together with the demonstration that β2-m-mediated multiple downstream converging signaling pathways, including AR, lipid, iron and ROS [31,36,42,43], could exert powerful influences on the fate of PCa cells and their clinical behavior.…”

“…Because genetic knockdown of β2-m or its receptor HFE drives the reversal of EMT with evidence of PCa cell death, we and others have employed anti-β2-m antibodies as reagents to treat both liquid [44,45] and solid [32,34,36,42] tumors in mice. While these antibodies have no observable effects on the growth of normal organs and cells, application of these antibodies caused remarkable remission of both liquid and solid tumors in experimental mice, compared to the effects of isotype-specific control antibodies [34,44,45].…”

“…Laboratory data support the hypothesis that the RANK-mediated signal network is the driving force for PCa bone metastasis. Based on current bone-directed targeting strategies, we suggest including the following targets downstream from the RANK-mediated signal network: 1) β2-m. As a pleiotropic signaling molecule for cancer growth and survival, anti-β2-m antibodies or drugs interfering with iron flux can be used in combination with chemotherapy or radiation therapy to enhance the cytotoxicity of antibodies or drugs in tumor cells [42]. 2) c-Met.…”