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IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo

机译：IAPP驱动的代谢重编程诱导体内p53缺陷型肿瘤消退

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摘要

TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) iso-forms of p63 and p73 structurally and functionally resemble p53, whereas the ΔN isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPPy the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the β cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.%肿瘤抑制因子p53在癌症中经常发生突变或丢失。来自小鼠模型的证据表明，肿瘤中p53活性的再激发能导致肿瘤消退，但正常p53活性的直接再激发尚未发展成治疗人类癌症的一个有效策略。在这篇论文中，Elsa Flores及同事通过小鼠实验显示，在没有p53的情况下，p53家族蛋白p63和p73的失活，会通过IAPP(islet amyloid polypeptide，亦称为amylin)的激发导致代谢重新编程和肿瘤消退。抗糖尿病药物pramlintide (amylin的一种类似物)在患p53缺失型胸腺淋巴瘤的小鼠中会造成肿瘤消退，说明这是也许可用来治疗p53缺失型癌症的一个新方法。
机译：TP53在人类癌症中通常会发生改变，并且Tp53的激活会抑制小鼠体内的肿瘤（TP53和Tp53也称为p53）。事实证明，该策略难以在治疗上实施，在这里，我们通过操纵p53家族成员Tp63和Tp73（分别称为p63和p73）来研究另一种策略。 p63和p73的带有酸性反式激活域（TA）的亚型在结构上和功能上类似于p53，而p63和p73的ΔN异构体（缺少酸性反式激活域）在癌症中经常过度表达，并且主要在显性中起作用。对抗p53，TAp63和TAp73的阴性反应可抑制其肿瘤抑制功能。 p53家族在促进肿瘤抑制（例如凋亡和自噬）的细胞过程中发生广泛相互作用，因此需要明确了解癌症中的这种相互作用才能治疗p53途径改变的肿瘤。在这里，我们显示p63或p73的ΔN亚型的缺失通过IAPPy的上调导致代谢重编程和p53缺陷型肿瘤的消退，而IAPPy是编码胰岛淀粉样多肽的基因，胰岛淀粉样多肽是胰岛素与β细胞共同分泌的37个氨基酸肽胰腺。我们发现IAPP参与这种肿瘤的消退，并且胰岛淀粉样多肽通过降钙素受体（CalcR）和受体活性修饰蛋白3（RAMP3）发挥功能，从而抑制糖酵解并诱导活性氧和细胞凋亡。普兰林肽是胰岛淀粉样多肽的合成类似物，目前用于治疗1型和2型糖尿病，在p53缺乏的胸腺淋巴瘤中引起肿瘤的快速消退，代表了针对p53缺乏的癌症的新策略。经常发生突变或丢失。来自小鼠模型的证据表明，肿瘤中p53活性的再激发能导致肿瘤消退，但正常p53活性的直接再激发尚未发展成治疗人类癌症的一个有效策略。在本文中，Elsa Flores及同事通过小鼠实验显示，在没有p53的情况下，p53家族蛋白p63和p73的失活，会通过IAPP（胰岛淀粉样多肽，亦称淀粉样蛋白）的引发诱导重新编程和肿瘤消退。抗糖尿病药物pramlintide（amylin的一种类似物）在患p53缺失型胸腺淋巴瘤的小鼠中会引起肿瘤消退，说明这是也允许治疗p53缺失型癌症的一个新方法。

著录项

  • 来源
    《Nature》 |2015年第7536期|626-630a2|共6页
  • 作者

    Avinashnarayan Venkatanarayan; Payal Raulji; William Norton; Deepavali Chakravarti; Cristian Coarfa; Xiaohua Su; Santosh K. Sandur; Marc S. Ramirez; Jaehuk Lee; Charles V. Kingsley; Eliot F. Sananikone; Kimal Rajapakshe; Katherine Naff; Jan Parker-Thornburg; James A. Bankson; Kenneth Y. Tsai; Preethi H. Gunaratne; Elsa R. Flores;

  • 作者单位

    Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas and 77030, USA;

    Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas and 77030, USA;

    Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA;

    Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas and 77030, USA;

    Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas and 77030, USA,Radiation Biology & Health Sciences Division, Bhabha Atomic Research Center, Mumbai 400085, India;

    Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas and 77030, USA;

    Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA;

    Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA;

    Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA;

    Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA,Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas and 77030, USA;

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