Reactivating p53 functions by suppressing its novel inhibitor iASPP: a potential therapeutic opportunity in p53 wild-type tumors.
Reactivating p53 functions by suppressing its novel inhibitor iASPP: a potential therapeutic opportunity in p53 wild-type tumors.
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DOI：
10.18632/oncotarget.4847
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发表时间：
2015-08-21
期刊：
影响因子：
--
通讯作者：
Sakuragi N
中科院分区：
文献类型：
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作者：
Dong P;Ihira K;Hamada J;Watari H;Yamada T;Hosaka M;Hanley SJ;Kudo M;Sakuragi N
尽管在50%的人类肿瘤中发现p53突变失活，但一部分肿瘤显示p53功能缺陷，但保留野生型（WT） p53。本文讨论了导致WT p53活性丧失的直接和间接机制。本文综述了WT p53抑制剂iASPP在促进肿瘤增殖、侵袭、耐药或耐辐射及转移等方面的作用。从治疗角度来看，我们强调了减少或阻断iASPP的microRNA-124、肽和小分子在治疗癌症方面的前景。在一系列人类肿瘤中，iASPP的高表达增强了肿瘤的增殖、侵袭性行为、对放疗/化疗的耐药性，并与不良预后相关。iASPP的过表达通过p53依赖和p53不依赖的机制加速肿瘤的发生和侵袭。MicroRNA-124直接靶向iASPP，抑制癌细胞的生长和侵袭性。p53衍生肽A34破坏iASPP-p53相互作用，恢复p53在癌细胞中的功能。小分子抑制iASPP磷酸化诱导p53依赖性细胞凋亡和生长抑制。iASPP在人类肿瘤中异常表达的机制有待进一步研究。通过靶向其新型抑制剂iASPP来重新激活WT p53功能，有望为治疗WT p53肿瘤提供潜在的治疗干预措施。
Although mutational inactivation of p53 is found in 50% of all human tumors, a subset of tumors display defective p53 function, but retain wild-type (WT) p53. Here, direct and indirect mechanisms leading to the loss of WT p53 activities are discussed. We summarize the oncogenic roles of iASPP, an inhibitor of WT p53, in promoting proliferation, invasion, drug or radiation-resistance and metastasis. From the therapeutic view, we highlight promising perspectives of microRNA-124, peptide and small molecules that reduce or block iASPP for the treatment of cancer. High iASPP expression enhances proliferation, aggressive behavior, the resistance to radiation/chemotherapy and correlates with poor prognosis in a range of human tumors. Overexpression of iASPP accelerates tumorigenesis and invasion through p53-dependent and p53-independent mechanisms. MicroRNA-124 directly targets iASPP and represses the growth and invasiveness of cancer cells. The disruption of iASPP-p53 interaction by a p53-derived peptide A34 restores p53 function in cancer cells. The inhibition of iASPP phosphorylation with small molecules induces p53-dependent apoptosis and growth suppression. The mechanisms underlying aberrant expression of iASPP in human tumors should be further investigated. Reactivating WT p53 functions by targeting its novel inhibitor iASPP holds promise for potential therapeutic interventions in the treatment of WT p53-containing tumors.