Inhibition of p53 and/or AKT as a new therapeutic approach specifically targeting ALT cancers.
10.1007/s13238-019-0634-z
- Author:
Yuanlong GE
1
;
Shu WU
1
;
Zepeng ZHANG
1
;
Xiaocui LI
1
;
Feng LI
1
;
Siyu YAN
1
;
Haiying LIU
1
;
Junjiu HUANG
1
;
Yong ZHAO
2
Author Information
1. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
2. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China. zhaoy82@mail.sysu.edu.cn.
- Publication Type:Journal Article
- Keywords:
AKT;
ALT;
DNA damage;
apoptosis;
p53;
telomeres
- From:
Protein & Cell
2019;10(11):808-824
- CountryChina
- Language:English
-
Abstract:
While the majority of all human cancers counteract telomere shortening by expressing telomerase, ~15% of all cancers maintain telomere length by a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). Here, we show that high load of intrinsic DNA damage is present in ALT cancer cells, leading to apoptosis stress by activating p53-independent, but JNK/c-Myc-dependent apoptotic pathway. Notably, ALT cells expressing wild-type p53 show much lower apoptosis than p53-deficient ALT cells. Mechanistically, we find that intrinsic DNA damage in ALT cells induces low level of p53 that is insufficient to initiate the transcription of apoptosis-related genes, but is sufficient to stimulate the expression of key components of mTORC2 (mTOR and Rictor), which in turn leads to phosphorylation of AKT. Activated AKT (p-AKT) thereby stimulates downstream anti-apoptotic events. Therefore, p53 and AKT are the key factors that suppress spontaneous apoptosis in ALT cells. Indeed, inhibition of p53 or AKT selectively induces rapid death of ALT cells in vitro, and p53 inhibitor severely suppresses the growth of ALT-cell xenograft tumors in mice. These findings reveal a previously unrecognized function of p53 in anti-apoptosis and identify that the inhibition of p53 or AKT has a potential as therapeutics for specifically targeting ALT cancers.
