Unknown

Dataset Information

0

RITA requires eIF2?-dependent modulation of mRNA translation for its anti-cancer activity.


ABSTRACT: Tumor protein 53 (p53, encoded by the TP53 gene) is a key tumor suppressor regulating cell fates in response to internal and external stresses. As TP53 is mutated or silenced in a majority of tumors, reactivation of p53 by small molecules represents a promising strategy in cancer therapeutics. One such agent is RITA (reactivation of p53 and induction of tumor cell apoptosis), which restores p53 expression in cells with hyperactive HDM2 and induces apoptosis. Yet, mechanisms underlying the anticancer activity of RITA are incompletely understood. Here we show that RITA suppresses mRNA translation independently of p53 by inducing eIF2? phosphorylation. Surprisingly, reactivation of p53 following RITA treatment is critically dependent on eIF2? phosphorylation. Moreover, inhibition of eIF2? phosphorylation attenuates pro-apoptotic and anti-neoplastic effects of RITA, while inducing phosphorylation of eIF2? enhances the anticancer activity of RITA. Collectively, these findings demonstrate that the translational machinery plays a major role in determining the antineoplastic activity of RITA, and suggest that combining p53 activators and translation modulators may be beneficial.

SUBMITTER: Ristau J 

PROVIDER: S-EPMC6838152 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

altmetric image

Publications

RITA requires eIF2α-dependent modulation of mRNA translation for its anti-cancer activity.

Ristau Johannes J   van Hoef Vincent V   Peuget Sylvain S   Zhu Jiawei J   Guan Bo-Jhih BJ   Liang Shuo S   Hatzoglou Maria M   Topisirovic Ivan I   Selivanova Galina G   Larsson Ola O  

Cell death & disease 20191107 11


Tumor protein 53 (p53, encoded by the TP53 gene) is a key tumor suppressor regulating cell fates in response to internal and external stresses. As TP53 is mutated or silenced in a majority of tumors, reactivation of p53 by small molecules represents a promising strategy in cancer therapeutics. One such agent is RITA (reactivation of p53 and induction of tumor cell apoptosis), which restores p53 expression in cells with hyperactive HDM2 and induces apoptosis. Yet, mechanisms underlying the antica  ...[more]

Similar Datasets

| S-EPMC4019499 | biostudies-literature
| S-EPMC5449617 | biostudies-literature
| S-EPMC3136507 | biostudies-literature
| S-EPMC5327398 | biostudies-literature
| S-EPMC5892948 | biostudies-literature
| S-EPMC5438615 | biostudies-literature
| S-EPMC316867 | biostudies-literature
2014-06-02 | E-GEOD-54581 | biostudies-arrayexpress
| S-EPMC6020024 | biostudies-literature
| S-EPMC6375727 | biostudies-literature