Androgen receptor survival signaling is blocked by anti-beta2-microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells.
ABSTRACT 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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- "AR is regulated by β2-microglobulin (β2-M), a component of the housekeeping major histocompatibility complex class I molecule found on prostate cancer cells, in a MAPK/ SREBP-1-dependent manner. Inhibition of β2-M by a selective antibody decreases the interaction between SREBP-1 and its binding site in the AR promoter region, resulting in decreased AR expression and lipogenesis by FASN . A new AR splice variant, AR8, was recently identified and is strongly expressed in castration resistant prostate cancer (CRPC). "
Article: Lipids and prostate cancer[Show abstract] [Hide abstract]
ABSTRACT: The role of lipid metabolism has gained particular interest in prostate cancer research. A large body of literature has outlined the unique upregulation of de novo lipid synthesis in prostate cancer. Concordant with this lipogenic phenotype is a metabolic shift, in which cancer cells use alternative enzymes and pathways to facilitate the production of fatty acids. These newly synthesized lipids may support a number of cellular processes to promote cancer cell proliferation and survival. Hence, de novo lipogenesis is under intense investigation as a therapeutic target. Epidemiologic studies suggest dietary fat may also contribute to prostate cancer; however, whether dietary lipids and de novo synthesized lipids are differentially metabolized remains unclear. Here, we highlight the lipogenic nature of prostate cancer, especially the promotion of de novo lipid synthesis, and the significance of various dietary lipids in prostate cancer development and progression.Prostaglandins & other lipid mediators 04/2012; 98(1-2):1-10. DOI:10.1016/j.prostaglandins.2012.03.003 · 2.86 Impact Factor
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ABSTRACT: Bone metastasis is one of the predominant causes of cancer lethality. This study demonstrates for the first time how β2-microglobulin (β2-M) supports lethal metastasis in vivo in human prostate, breast, lung, and renal cancer cells. β2-M mediates this process by activating epithelial to mesenchymal transition (EMT) to promote lethal bone and soft tissue metastases in host mice. β2-M interacts with its receptor, hemochromatosis (HFE) protein, to modulate iron responsive pathways in cancer cells. Inhibition of either β2-M or HFE results in reversion of EMT. These results demonstrate the role of β2-M in cancer metastasis and lethality. Thus, β2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy.Cancer Research 03/2011; 71(7):2600-10. DOI:10.1158/0008-5472.CAN-10-3382 · 9.28 Impact Factor
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ABSTRACT: Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10-20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression.Journal of Molecular Endocrinology 04/2011; 47(1):R25-41. DOI:10.1530/JME-11-0018 · 3.62 Impact Factor