Iron addiction: a novel therapeutic target in ovarian cancer.
Iron addiction: a novel therapeutic target in ovarian cancer.
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DOI：
10.1038/onc.2017.11
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发表时间：
2017-07-20
期刊：
影响因子：
8
通讯作者：
Torti SV
中科院分区：
文献类型：
--
作者：
Basuli D;Tesfay L;Deng Z;Paul B;Yamamoto Y;Ning G;Xian W;McKeon F;Lynch M;Crum CP;Hegde P;Brewer M;Wang X;Miller LD;Dyment N;Torti FM;Torti SV
卵巢癌是一种致命的恶性肿瘤，30多年来没有看到重大的治疗进展。我们证明卵巢癌表现出铁代谢的靶向改变。在高级别而非低级别浆液性卵巢癌患者的肿瘤组织中，铁外排泵膜铁转运蛋白（FPN）减少，铁输入者转铁蛋白受体（TFR 1）增加。在卵巢癌肿瘤起始细胞（TIC）的遗传模型中观察到FPN减少和TFR1增加的类似情况。这些变化的最终结果是过量细胞内铁的积累和增殖对铁的依赖性增强。细胞内铁的强制性减少在体外降低卵巢癌TIC的增殖，并且在体内抑制肿瘤生长和肿瘤细胞的腹膜内传播。机制研究表明，铁通过促进基质金属蛋白酶的表达和IL 6的合成的侵袭，增加转移扩散。我们表明，卵巢癌肿瘤起始细胞的铁依赖性使它们在体内对诱导铁依赖性细胞死亡（铁凋亡）的药物以及铁螯合剂非常敏感，从而产生了一种可用于治疗的代谢脆弱性。
Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of IL6. We show that the iron dependence of ovarian cancer tumor initiating cells renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.
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影响因子：
7.3
作者：
Leong, Huei San;Galletta, Laura;Bowtell, David
通讯作者：
Bowtell, David
影响因子：
7.3
作者：
Ahmed, Ashour Ahmed;Etemadmoghadam, Dariush;Temple, Jillian;Lynch, Andy G.;Riad, Mohamed;Sharma, Raghwa;Stewart, Colin;Fereday, Sian;Caldas, Carlos;DeFazio, Anna;Bowtell, David;Brenton, James D.
通讯作者：
Brenton, James D.
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
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作者：
通讯作者：
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