Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells
Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells
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DOI：
10.1074/jbc.m109.092759
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发表时间：
2010-03-12
影响因子：
4.8
通讯作者：
Chung, Leland W. K.
中科院分区：
文献类型：
--
作者：
Huang, Wen-Chin;Zhau, Haiyen E.;Chung, Leland W. K.
在人雄激素受体（AR）启动子5 '端及其结合转录因子SREBP-1中发现了一个新的顺式作用元件--固醇调节元件结合蛋白-1（SREBP-1）结合位点，它在AR阳性的人前列腺癌细胞中调节AR的转录。我们进一步表征了一种新型抗β 2-微球蛋白单克隆抗体（β 2 MmAb）的分子机制，该抗体在许多人和小鼠癌细胞系中诱导大量细胞死亡，阻断了人前列腺癌细胞中的多种细胞信号传导途径。β 2 M mAb通过失活MAPK和SREBP-1降低AR表达。通过MAPK的失活，β 2 M mAb降低前列腺癌细胞的增殖和存活。通过抑制SREBP-1，β 2 M mAb降低了脂肪酸和脂质水平，这是细胞膜、细胞信号传导介质和能量代谢的组成部分。这些结果首次提供了MAPK和SREBP-1介导的β 2 M细胞内信号传导轴之间的分子联系，并涉及脂质信号传导，共同调节AR表达和功能。通过β 2 M mAb拮抗β 2 M可能是一种有效的治疗方法，同时靶向与MAPK、SREBP-1和AR会聚的多个下游信号通路，对控制前列腺癌细胞生长、存活和进展很重要。
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-beta 2-microglobulin monoclonal antibody (beta 2MmAb), 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. beta 2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, beta 2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, beta 2M 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 beta 2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing beta 2M by beta 2M 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.