Androgen Receptor Survival Signaling Is Blocked by Anti- 2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2010; 285(11):7947-56. DOI: 10.1074/jbc.M109.092759
Source: PubMed


A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5'-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-beta2-microglobulin monoclonal antibody (beta2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. beta2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, beta2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, beta2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the beta2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing beta2M by beta2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression.

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    • "For c-Myc inhibition, LNCaP cells were pretreated with 40 μM 10058-F4 c-Myc inhibitor for 4 h before treatment with RANKL. The luciferase promoter assay was conducted as described previously (Huang et al. 2010). "
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    ABSTRACT: Prostate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model to study the mechanisms underlying the metastatic process. Here we report that receptor activator of NF-κB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor deletion/interference assays identified common transcription factor complexes (TFs), c-Myc/Max and AP4, as critical regulatory nodes. RANKL-RANK signaling activated a number of master regulator TFs that control the epithelial-mesenchymal transition (EMT) (Twist1, Slug, Zeb1, Zeb2), stem cell properties (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine differentiation (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network, minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non-tumorigenic LNCaP cells to express RANKL, c-Met/activated c-Met, while downregulating AR expression. These initially non-tumorigenic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK-RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic cells.
    Endocrine Related Cancer 01/2014; 21(2). DOI:10.1530/ERC-13-0548 · 4.81 Impact Factor
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    • "In prostate cancer, the expression of SREBPs and their targets changes during cancer progression (Ettinger et al., 2004). Interestingly, SREBP1 was found to regulate the transcription of the androgen receptor (AR) gene (Huang et al., 2010), and to promote proliferation, migration and invasion in prostate cancer (Huang et al., 2012). Furthermore, certain subtypes of glioblastoma multiforme (GBM) that express an activated mutant form of the epithelial growth factor receptor (EGFR) also display high levels of nuclear SREBP1. "
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    ABSTRACT: An increased rate of lipid synthesis in cancerous tissues has long been recognised as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids to cellular transformation, tumour development and tumour progression, as well as their potential role in facilitating the spread of cancerous cells to secondary sites, are not yet fully understood. In this article, we review the recent findings that support the importance of lipid synthesis and metabolism in tumorigenesis. Specifically, we explore the role of aberrant lipid biosynthesis in cancer cell migration and invasion, and in the induction of tumour angiogenesis. These processes are crucial for the dissemination of tumour cells and formation of metastases, which constitute the main cause of cancer mortality.
    Disease Models and Mechanisms 11/2013; 6(6):1353-63. DOI:10.1242/dmm.011338 · 4.97 Impact Factor
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    • "Yang et al. [12] demonstrated that mAbs induce apoptosis in myeloma cells by recruiting MHC class I molecules to lipid rafts and by excluding growth factor receptors. Similarly, Huang et al. [13] revealed that β2M-specific mAb decreases lipid levels in prostate cancer cells to make a link between β2M-mediated intracellular signaling axis and lipid rafts in the cell membrane. This may explain why β2M mAbs-induced apoptosis in cancers is mediated via quite similar signaling pathways – the inhibition of PI3K/Akt, MAPK, and Bcl-2, and the activation of caspases-dependent cascade – supporting the role of β2M as a mitogenic factor. "
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    ABSTRACT: β2-microglobulin (β2M) functions as a chaperon to maintain structural stability of MHC class I complex that is associated with antigen presentation to cytotoxic (CD8+) T lymphocytes. Cancerous cells in β2M loss-of-function are thought to avoid immune surveillance. As increased level of β2M present in tissue/serum is significantly associated with tumor status in various cancers, β2M may become an important prognostic and survival factor in a range of malignancies. It is believed that β2M acts as hormone-like molecule to trigger a pleiotropic signaling via a ligand-to-receptor binding mechanism. Anti- β2M monoclonal antibodies successfully induce apoptosis in malignant cells, suggesting a surprising therapeutic approach. Of note, β2M is largely localized in the cytoplasm of advanced oral cavity squamous cell carcinoma (OCSCC), in contrast to that in the plasma membrane of normal oral mucosa. This suggests that β2M-derived intracellular signaling might be preceded by its accumulation in the cytoplasm of epithelial cells of tumors. Hence, translocation of β2M from cell surface to cytoplasm in advanced tumors may shed light on the mechanism of β2M-mediated tumorigenesis.
    10/2013; 19:271-3. DOI:10.12659/MSMBR.889457
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