通过蛋白质翻译控制乳腺癌细胞可塑性

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原标题:通过蛋白质翻译控制乳腺癌细胞可塑性

肿瘤可塑性可使癌细胞获得肿瘤生长必需的干细胞样特性,也给肿瘤治疗带来了复发、转移、耐药等诸多挑战。

2020年5月19日,英国《自然》旗下《自然通讯》在线发表加拿大西安大略大学、艾伯塔大学、麦吉尔大学、圭尔夫大学、维多利亚女王大学、美国凯斯西储大学、查尔斯河(查士利华)实验室德国弗赖堡分部的研究报告,探讨了通过蛋白质翻译控制乳腺癌可塑性的具体机制和治疗策略。

该研究发现,在乳腺癌细胞中,未分化胚胎干细胞转录因子编码基因NANOG、上皮钙黏着蛋白转录因子(又被形象地称为蜗牛蛋白)编码基因SNAIL、转化生长因子β编码基因NODAL转录产物信使核糖核酸表现出以不同5'非翻译区为特征的多种异构体,在肿瘤缺氧微环境刺激下,这些异构体可被翻译为对应的蛋白质。对应蛋白质的不断增多,能诱发肿瘤细胞的可塑性,向干细胞样表现型转换。

机制分析表明,哺乳动物雷帕霉素靶蛋白mTOR抑制剂和化疗药物可诱发类似缺氧刺激下的NANOG、SNAIL、NODAL信使核糖核酸异构体翻译作用激活,从而产生干细胞样表现型。

利用综合应激反应抑制剂ISRIB等逆转真核起始因子eIF2α磷酸化所致翻译重编程的药物可以克服上述影响,表明综合应激反应能够促进乳腺癌可塑性。

因此,该研究结果揭示了诱发乳腺癌细胞可塑性的具体机制,并为克服耐药和消除转移的治疗策略奠定了分子学基础。

Nat Commun. 2020 May 19. [Epub ahead of print]

Translational control of breast cancer plasticity.

Michael Jewer, Laura Lee, Matthew Leibovitch, Guihua Zhang, Jiahui Liu, Scott D. Findlay, Krista M. Vincent, Kristofferson Tandoc, Dylan Dieters-Castator, Daniela F. Quail, Indrani Dutta, Mackenzie Coatham, Zhihua Xu, Aakshi Puri, Bo-Jhih Guan, Maria Hatzoglou, Andrea Brumwell, James Uniacke, Christos Patsis, Antonis Koromilas, Julia Schueler, Gabrielle M. Siegers, Ivan Topisirovic, Lynne-Marie Postovit.

University of Western Ontario, London, ON, Canada; University of Alberta, Edmonton, AB, Canada; McGill University, Montreal, QC, Canada; University of Guelph, Guelph, ON, Canada; Queen's University, Kingston, ON, Canada; Case Western Reserve University, Cleveland, OH, USA; Charles River Discovery Research Services Germany, Freiburg, Germany.

Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG, SNAIL and NODAL trans manifest multiple isoforms characterized by different 5' Untranslated Regions (5'UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. The accumulation of the corresponding proteins induces plasticity and "fate-switching" toward stem cell-like phenotypes. Mechanistically, we observe that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG, SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem-cell-like phenotypes. These effects are overcome with drugs that antagonize translational reprogramming caused by eIF2α phosphorylation (e.g. ISRIB), suggesting that the Integrated Stress Response drives breast cancer plasticity. Collectively, our findings reveal a mechanism of induction of plasticity of breast cancer cells and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis.