The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance

Peter P. Ruvolo
{"title":"The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance","authors":"Peter P. Ruvolo","doi":"10.1016/j.bbacli.2016.08.002","DOIUrl":null,"url":null,"abstract":"<div><p>Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both “On” and “Off” switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the “On” position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective “Off” switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance.</p></div>","PeriodicalId":72344,"journal":{"name":"BBA clinical","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbacli.2016.08.002","citationCount":"117","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"BBA clinical","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2214647416300320","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 117

Abstract

Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both “On” and “Off” switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the “On” position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective “Off” switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance.

Abstract Image

Abstract Image

Abstract Image

癌症信号传导中断开的“关闭”开关:PP2A作为肿瘤发生、耐药性和免疫监视的调节因子
信号转导途径的异常激活可以将正常细胞转化为恶性细胞,并可以赋予癌细胞抵抗治疗的生存特性。一系列不同的级联反应与多种癌症有关,包括丝氨酸/苏氨酸激酶介导的癌症,如RAS、PI3K/AKT和PKC。信号转导是一个涉及“开”和“关”开关的动态过程。RAS或PI3K的激活突变可以被视为开关被卡在“开”位置,从而通过生存和/或增殖途径继续发出信号。另一方面,蛋白磷酸酶如PP2A家族的失活可以被视为有缺陷的“关闭”开关,同样可以激活这些途径。治疗靶向PP2A的一个问题是,该酶是一种异质三聚体,因此药物靶向涉及复杂的结构。更重要的是,由于PP2A异构体通常作为肿瘤抑制因子,人们希望激活这些酶而不是抑制它们。细胞抑制剂如SET和CIP2A在癌症中的作用的阐明表明,靶向这些蛋白可以通过涉及PP2A激活的机制产生治疗效果。此外,FTY-720等药物可以直接激活PP2A亚型。本综述将涵盖PP2A在癌细胞中作为肿瘤抑制因子的作用以及作为影响耐药和免疫监视过程的中介的现状。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信