Induction of the p53 Tumor Suppressor in Cancer Cells through Inhibition of Cap-Dependent Translation

被引：16

作者：

Harris, Benjamin R. E. ^{[1
]}

Wang, Defeng ^{[1
,4
]}

Zhang, Ye ^{[1
]}

Ferrari, Marina ^{[1
]}

Okon, Aniekan ^{[3
]}

Cleary, Margot P. ^{[1
,2
]}

Wagner, Carston R. ^{[2
,3
]}

Yang, Da-Qing ^{[1
,2
]}

机构：

[1] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA

[2] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55455 USA

[3] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA

[4] Hebei Engn Univ, Affiliated Hosp, Handan, Hebei, Peoples R China

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2018年 / 38卷 / 10期

基金：

美国国家卫生研究院;

关键词：

4EGI-1; p53; eIF4E; IRES; INITIATION-FACTOR EIF4E; RNA-BINDING PROTEIN; ENTRY SITE; APOPTOSIS; RESVERATROL; EXPRESSION; MECHANISM; COMPLEX; STRESS; 4EGI-1;

D O I：

10.1128/MCB.00367-17

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The p53 tumor suppressor plays a critical role in protecting normal cells from malignant transformation. Development of small molecules to reactivate p53 in cancer cells has been an area of intense research. We previously identified an internal ribosomal entry site (IRES) within the 5' untranslated region of p53 mRNA that mediates translation of the p53 mRNA independent of cap-dependent translation. Our results also show that in response to DNA damage, cells switch from cap-dependent translation to cap-independent translation of p53 mRNA. In the present study, we discovered a specific inhibitor of cap-dependent translation, 4EGI-1, that is capable of inducing the accumulation of p53 in cancer cells retaining wild-type p53. Our results show that 4EGI-1 causes an increase in p53 IRES activity, leading to increased translation of p53 mRNA. We also observed that 4EGI-1 induces cancer cell apoptosis in a p53-dependent manner. Furthermore, 4EGI-1 induces p53 in cancer cells without causing DNA double-strand breaks. In conclusion, we discovered a mechanistic link between inhibition of cap-dependent translation and enhanced p53 accumulation. This leads to apoptosis of cancer cells without causing collateral damage to normal cells, thus providing a novel and effective therapeutic strategy for cancer.

引用

页数：14

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