Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells
Inhibition of macrophage migration inhibitory factor or its receptor (CD74) attenuates growth and invasion of DU-145 prostate cancer cells
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DOI：
10.4049/jimmunol.177.12.8730
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发表时间：
2006-12-15
影响因子：
4.4
通讯作者：
Vera, Pedro L.
中科院分区：
文献类型：
--
作者：
Meyer-Siegler, Katherine L.;Iczkowski, Kenneth A.;Vera, Pedro L.
巨噬细胞迁移抑制因子（MIF）是一种促炎细胞因子，在前列腺癌中过度表达，但 MIF 对肿瘤细胞产生影响的机制仍不清楚。 MIF 与其识别的膜受体 CD74 相互作用，并与 CD44 结合，导致 ERK 1/2 激活。因此，我们假设前列腺癌细胞 CD74 和 MIF 过度表达的增加或表面定位调节了肿瘤细胞的活力。与正常人前列腺或良性前列腺上皮细胞相比，前列腺癌细胞系（LNCaP 和 DU-145）的 MIF 基因表达和蛋白质水平增加（p < 0.01）。虽然 MIF、CD74 和 CD44 变体 9 表达。 CD74 在雄激素依赖性 (LNCaP) 和雄激素非依赖性 (DU-145) 前列腺癌细胞中均增加，但仅在雄激素非依赖性 (DU-145) 前列腺癌细胞中检测到细胞表面 CD74。因此，旨在阻断CD74和/或MIF的治疗（例如，通过RNA干扰抑制MIF或CD74表达或用抗MIF或抗CD74中和抗体或MIF特异性抑制剂ISO-1治疗）仅对雄激素非依赖性前列腺癌细胞（DU-145）有效，导致细胞增殖、MIF蛋白分泌和侵袭减少。在 DU-145 异种移植物中，ISO-1 显着减少肿瘤体积和肿瘤血管生成。我们的结果显示，DU-145 前列腺癌细胞中的细胞表面 CD74 较多，可与 MIF 结合，从而介导 MIF 激活的信号转导。 DU-145 前列腺癌细胞的生长和侵袭需要 MIF 激活的信号转导途径，而这对于雄激素依赖性前列腺细胞的生长或活力来说并不是必需的。因此，在配体（MIF）或受体（CD74）处阻断MIF可能为雄激素非依赖性前列腺癌提供新的、有针对性的特异性疗法。
Macrophage migration inhibitory factor, (MIF), a proinflammatory cytokine, is overexpressed in prostate cancer, but the mechanism by which MIF exerts effects on tumor cells remains undetermined. MIF interacts with its identified membrane receptor, CD74, in association with CD44, resulting in ERK 1/2 activation. Therefore, we hypothesized that increased expression or surface localization of CD74 and MIF overexpression by prostate cancer cells regulated tumor cell viability. Prostate cancer cell lines (LNCaP and DU-145) had increased MIF gene expression and protein levels compared with normal human prostate or benign prostate epithelial cells (p < 0.01). Although MIF, CD74, and CD44 variant 9 expression. were increased in both andro-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells, cell surface of CD74 was only detected in androgen-independent (DU-145) prostate cancer cells. Therefore, treatments aimed at blocking CD74 and/or MIF (e.g., inhibition of MIF or CD74 expression by RNA interference or treatment with anti-MIF- or anti-CD74- neutralizing Abs or MIF-specific inhibitor, ISO-1) were only effective in androgen-independent prostate cancer cells (DU-145), resulting in decreased cell proliferation, MIF protein secretion, and invasion. In DU-145 xenografts, ISO-1 significantly decreased tumor volume and tumor angiogenesis. Our results showed greater cell surface CD74 in DU-145 prostate cancer cells that bind to MIF and, thus, mediate MIF-activated signal transduction. DU-145 prostate cancer cell growth and invasion required MIF activated signal transduction pathways that were not necessary for growth or viability of androgen-dependent prostate cells. Thus, blocking MIF either at the ligand (MIF) or receptor (CD74) may provide new, targeted specific therapies for androgen-independent prostate cancer.