摘要
While the majority of all human cancers court teract 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-IVIyc-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 sponta?neous 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 antiapoptosis and identify that the inhibition of p53 or AKT has a potential as therapeutics for specifically targeting ALT cancers.
基金
This work was supported by the National Natural Science Foundation of China(Grants Nos.31571410,31701196,81702756,31570827 and 81771506)
the National Key R&D Program of China(2018YFA0107000)
and Guangzhou Municipal People's Livelihood Science and Technology Plan(201803010108 and 201604016111)
the China Postdoctoral Science Foundation(2016M600696)
and the Fun dame ntal Research Funds for the Central Un iversities(171gpy97 and 18lgpy52).
