IAPP-driven metabolic reprogramming induces regression of
p53-deficient tumours in vivo
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) isoforms 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 IAPP, 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.
Nature：曲线救国，攻克p53缺陷肿瘤
发布时间：2014-12-01 00:00 文章来源： 作者：
导读：近日，发表在《自然》杂志上的一项研究中，科学家们发现，改变被称作为肿瘤抑制基因的p53基因家族成员，可导致p53缺陷或是完全缺失p53的肿瘤迅速消退。研究结果表明，影响相同基因-蛋白质信号通路的一些现有糖尿病药物有可能可以有效地治疗癌症。
科学家们发现，改变被称作为肿瘤抑制基因的p53基因家族成员，可导致p53缺陷或是完全缺失p53的肿瘤迅速消退。研究结果表明，影响相同基因-蛋白质信号通路的一些现有糖尿病药物有可能可以有效地治疗癌症。
来自德克萨斯大学MD安德森癌症中心的这项研究证实，在体内可以操控p63和p73基因来上调IAPP蛋白的水平。IAPP是对机体代谢葡萄糖的能力极为重要的一种蛋白。市场上已有的一些糖尿病药物中就包含有IAPP。
这项发表在11月17日《自然》（Nature）杂志上的研究，是由德克萨斯大学MD安德森癌症中心的分子和细胞肿瘤学副教授Elsa R. Flores博士所领导。其将焦点放在了因独特的遗传组成，而能够导致肿瘤消退或刺激肿瘤生长的p63和p73基因上。
Flores说：“P53在大多数的人类癌症中均发生了改变，在小鼠的体内重激活p53可以抑制肿瘤。但事实证明在临床上实施这一策略存在困难。我们检测了一种替代方法：操控p53家族成员p63和p73。”
在 这篇文章中，Flores描述了p63和p73的两个“对立”版本：在肿瘤抑制方面它们之间背道而驰。一个版本，即p63和p73的TA(带有反式激活结 构域)亚型在结构和功能上均与p53相似，能够抑制肿瘤。而另一个版本，即p63和p73的ΔN亚型（缺乏反式激活结构域）实际上阻碍了p53的抑制肿瘤 生长的效应。反式激活结构域是存在于称作为转录因子的蛋白质中的特殊区域，转录因子可进一步影响下游的细胞反应。
Flores说：“p53家族在促进肿瘤抑制的一些细胞过程中广泛地互作。因此，治疗p53改变的肿瘤必须清楚地理解癌症中的这一相互作用。”
通过删除缺乏反式激活结构域的p63和p73版本，Flores的研究小组发现他们能够在代谢上重编程细胞，由此阻止并逆转p53缺陷肿瘤的癌症进展。这是 通过提高IAPP的水平来实现的。IAPP是对于机体利用胰岛素至关重要的一个基因。IAPP编码了与胰岛素共分泌的氨基酸链——胰淀素 (Amylin)。Flores认为要试图开发出针对p53缺陷肿瘤的新治疗方法IAPP具有重要的意义。
Flores说：“我们发现IAPP与肿瘤消退有关，IAPP基因编码的胰淀素终止了细胞代谢葡萄糖的能力，导致了程序性细胞死亡。普兰林肽（Pramlintide）是一种合成的胰淀素，当前用于治疗1型和2型糖尿病。在p53缺陷的胸腺淋巴瘤中普兰林肽引起了快速的肿瘤消退。”
Flores在p53删除和突变的各种人类癌细胞系中测试了普兰林肽，发现这种药物能够高度有效地抑制葡萄糖代谢，引起程序性细胞死亡。
Flores说：“这代表了靶向p53缺陷和突变癌症的一种新策略。”她和她的研究小组还鉴别了在p53缺陷和突变的肿瘤细胞上普兰林肽诱导肿瘤消退必需的一些关键受体。这些受体为确定普兰林肽将能否有效地治疗p53删除或突变癌症患者，提供了一个潜在的预后标记物。”
原文摘要：
IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo
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) isoforms 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 IAPP, 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.
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13910.html