Effects of Ferroportin-Mediated Iron Depletion in Cells Representative of Different Histological Subtypes of Prostate Cancer
Effects of Ferroportin-Mediated Iron Depletion in Cells Representative of Different Histological Subtypes of Prostate Cancer
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DOI：
10.1089/ars.2017.7023
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发表时间：
2017-12-11
影响因子：
6.6
通讯作者：
Torti, Frank M.
中科院分区：
文献类型：
--
作者：
Deng, Zhiyong;Manz, David H.;Torti, Frank M.
目的：膜铁转运蛋白（FPN）是一种铁输出蛋白，在细胞和全身铁代谢中起重要作用。我们以前的工作已经证明FPN在前列腺肿瘤中减少。我们试图确定FPN在前列腺癌cells. Results中调节的分子通路：我们发现，FPN的过表达通过激活不同但会聚的通路在代表前列腺癌多种组织学亚型的细胞中诱导深远的影响。FPN的诱导诱导自噬并激活转录因子肿瘤蛋白53（p53）和Kruppel样因子6（KLF6）及其共同的下游靶点，细胞周期蛋白依赖性激酶抑制剂1A（p21）。FPN还诱导细胞周期停滞和应激诱导的DNA损伤基因。FPN的作用归因于其对细胞内铁的作用，并且可以用铁螯合剂再现。重要的是，FPN的表达不仅抑制了所有研究的前列腺癌细胞的增殖，而且还减少了来自去势抵抗性腺癌C4 - 2细胞的肿瘤在vivo.Innovation的生长：我们使用一种新的FPN表达模型来询问前列腺癌细胞中铁耗竭引发的分子途径。由于前列腺癌包括不同的亚型，具有高度可变的临床过程，我们进一步探讨组织病理学亚型如何影响对铁耗竭的反应。我们证明，来自不同组织病理学亚型的前列腺癌细胞激活响应FPN介导的铁耗竭的会聚途径。这些途径的激活是足以显着减少治疗难治性C4 - 2前列腺肿瘤的生长在vivo.Conclusions：我们的研究结果可以解释为什么FPN是显着抑制癌细胞，他们认为，FPN激动剂可能是有益的前列腺癌的治疗。
Aims: Ferroportin (FPN) is an iron exporter that plays an important role in cellular and systemic iron metabolism. Our previous work has demonstrated that FPN is decreased in prostate tumors. We sought to identify the molecular pathways regulated by FPN in prostate cancer cells.Results: We show that overexpression of FPN induces profound effects in cells representative of multiple histological subtypes of prostate cancer by activating different but converging pathways. Induction of FPN induces autophagy and activates the transcription factors tumor protein 53 (p53) and Kruppel-like factor 6 (KLF6) and their common downstream target, cyclin-dependent kinase inhibitor 1A (p21). FPN also induces cell cycle arrest and stress-induced DNA-damage genes. Effects of FPN are attributable to its effects on intracellular iron and can be reproduced with iron chelators. Importantly, expression of FPN not only inhibits proliferation of all prostate cancer cells studied but also reduces growth of tumors derived from castrate-resistant adenocarcinoma C4-2 cells in vivo.Innovation: We use a novel model of FPN expression to interrogate molecular pathways triggered by iron depletion in prostate cancer cells. Since prostate cancer encompasses different subtypes with a highly variable clinical course, we further explore how histopathological subtype influences the response to iron depletion. We demonstrate that prostate cancer cells that derive from different histopathological subtypes activate converging pathways in response to FPN-mediated iron depletion. Activation of these pathways is sufficient to significantly reduce the growth of treatment-refractory C4-2 prostate tumors in vivo.Conclusions: Our results may explain why FPN is dramatically suppressed in cancer cells, and they suggest that FPN agonists may be beneficial in the treatment of prostate cancer.