陳志南、姜學軍團隊揭示癌細胞鐵死亡分子機制

陳志南、姜學軍團隊揭示癌細胞鐵死亡分子機制

作者：

小柯機器人

發布時間：2019/8/15 14:35:10

美國紀念斯隆凱特琳癌症中心姜學軍和中國空軍醫科大學陳志南研究團隊合作取得一項新進展。他們的研究發現細胞間相互作用通過NF2-YAP信號影響癌細胞鐵死亡。相關論文於2019年8月15日發表於國際學術期刊《自然》上。

研究人員發現，鐵死亡可以通過鈣粘蛋白介導的細胞間相互作用進行非細胞自主調控。在上皮細胞中，由E-鈣粘蛋白介導的這種相互作用通過激活細胞內NF2（也稱為merlin）和Hippo信號傳導途徑來抑制鐵死亡。拮抗該信號軸使得原癌基因轉錄共激活因子YAP通過上調幾種鐵死亡調節蛋白（包括ACSL4和TFRC）來促進鐵死亡。這一發現為具有間充質或轉移性癌細胞對鐵死亡高度敏感的觀察結果提供了機制見解。值得注意的是，類似的機制也調節一些非上皮細胞中的鐵死亡。最後，腫瘤抑制因子NF2的遺傳失活（間皮瘤中常見的致瘤事件），使得惡性間皮瘤的原位小鼠模型中的癌細胞對鐵死亡更敏感。這些研究結果證明了細胞間相互作用和細胞內NF2-YAP信號在決定鐵蛋白死亡中的作用，並且還發現NF2-YAP信號通路中的惡性突變可以預測癌細胞對未來鐵死亡誘導療法的響應性。

鐵死亡（ferroptosis）是由細胞代謝和鐵依賴性脂質過氧化驅動的細胞死亡過程，與缺血性器官損傷和癌症等疾病有關。穀胱甘肽過氧化物酶4（GPX4）是一種中樞調節者，通過中和脂質過氧化物（細胞代謝的副產物）來保護細胞。直接抑制GPX4，或通過耗盡其底物穀胱甘肽或穀胱甘肽的來源（如半胱氨酸）進行間接抑制，可引發鐵死亡。鐵死亡有助於幾種腫瘤抑制因子如p53，BAP1和延胡索酸酶的抗腫瘤功能。與預想相反的是，間充質癌細胞對鐵死亡很敏感，這些細胞易於轉移，並且通常對各種治療具有抗性。

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陳志南

陳志南，中國工程院院士，細胞生物學與生物藥物專家，空軍軍醫大學（第四軍醫大學）細胞生物學國家重點學科主任。長期從事炎-癌相關分子CD147系列研究，對腫瘤相關分子CD147在癌進展中的多時相、多階段和多節點的分子調控機制的原創性研究和轉化應用研究處於國際領先地位。（據中國工程院）

姜學軍

姜學軍，美國紀念斯隆-凱特林癌症中心姜學軍實驗室主任。主要研究方向：程序性細胞死亡、分子機制及其在腫瘤發生中的作用。（據美國紀念斯隆-凱特林癌症中心）

附：英文原文

Title: Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling

Author: Jiao Wu, Alexander M. Minikes, Minghui Gao, Huijie Bian, Yong Li, Brent R. Stockwell, Zhi-Nan Chen, Xuejun Jiang

Issue&Volume: Volume 572 Issue 7769

Abstract: Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage and cancer. The enzyme glutathione peroxidase 4 (GPX4) is a central regulator of ferroptosis, and protects cells by neutralizing lipid peroxides, which are by-products of cellular metabolism. The direct inhibition of GPX4, or indirect inhibition by depletion of its substrate glutathione or the building blocks of glutathione (such as cysteine), can trigger ferroptosis. Ferroptosis contributes to the antitumour function of several tumour suppressors such as p53, BAP1 and fumarase. Counterintuitively, mesenchymal cancer cellswhich are prone to metastasis, and often resistant to various treatmentsare highly susceptible to ferroptosis. Here we show that ferroptosis can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin suppress ferroptosis by activating the intracellular NF2 (also known as merlin) and Hippo signalling pathway. Antagonizing this signalling axis allows the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis by upregulating several ferroptosis modulators, including ACSL4 and TFRC. This finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroptosis. Notably, a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, genetic inactivation of the tumour suppressor NF2, a frequent tumorigenic event in mesothelioma, rendered cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Our results demonstrate the role of intercellular interactions and intracellular NF2YAP signalling in dictating ferroptotic death, and also suggest that malignant mutations in NF2YAP signalling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies.

DOI: 10.1038/s41586-019-1426-6

Source: https://www.nature.com/articles/s41586-019-1426-6