Journal Article
. 2018 Aug; 34(2):298-314.e7.
doi: 10.1016/j.ccell.2018.07.004.

Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion

Ramona Schulz-Heddergott 1 Nadine Stark 1 Shelley J Edmunds 1 Jinyu Li 2 Lena-Christin Conradi 3 Hanibal Bohnenberger 4 Fatih Ceteci 5 Florian R Greten 5 Matthias Dobbelstein 6 Ute M Moll 7 
Affiliations
  • PMID: 30107178
  •     52 References
  •     59 citations

Abstract

Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.

Keywords: CRC; GOF; Hsp90; Stat3; azoxymethane (AOM)/dextrane sodium sulfate (DSS)-induced CRC model; cancer cell invasion; colorectal cancer; gain-of-function; genetic APC intestinal cancer model; heat shock protein 90; mutant p53; mutp53; signal transducer and activator of transcription 3.

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lncRNA GAU1 Induces GALNT8 Overexpression and Potentiates Colorectal Cancer Progression.
Xuemei Tang, Haoyu Ruan, +3 authors, Ming Guan.
Gastroenterol Res Pract, 2021 Jul 10; 2021. PMID: 34239555    Free PMC article.
NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network.
Eleonora Mammarella, Carlotta Zampieri, +2 authors, Ivano Amelio.
Biol Direct, 2021 Aug 06; 16(1). PMID: 34348766    Free PMC article.
Systematic identification of novel cancer genes through analysis of deep shRNA perturbation screens.
Hesam Montazeri, Mairene Coto-Llerena, +13 authors, Charlotte K Y Ng.
Nucleic Acids Res, 2021 Jul 28; 49(15). PMID: 34313788    Free PMC article.
Attenuation of p53 mutant as an approach for treatment Her2-positive cancer.
Olga Fedorova, Alexandra Daks, +4 authors, Nikolai Barlev.
Cell Death Discov, 2021 Oct 11; 6(1). PMID: 34628470
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Ins and Outs of Heat Shock Proteins in Colorectal Carcinoma: Its Role in Carcinogenesis and Therapeutic Perspectives.
Batoul Abi Zamer, Waseem El-Huneidi, Mohamed Ahmed Eladl, Jibran Sualeh Muhammad.
Cells, 2021 Nov 28; 10(11). PMID: 34831085    Free PMC article.
Review.