Inhibition of p53 and/or AKT as a new therapeutic approach specifically targeting ALT cancers

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.

Correction to:Inhibition of p53 and/or AKT as a new therapeutic approach specifically targeting ALT cancers

Figure 4.AKT is phosphorylated in p53>dependent manner in ALT cells.(A)Western blot determination of total and phosphorylated AKT(S473)in p53-positive(VA13,U20S)and p53-defective(SAOS2,SKLU-1)ALT cells.(B)Knockdown of p53 in U20S or moderate expression of p53 in SAOS2 induces down or up-regulation of p-AKT,respectively.(C)Knockdown of ATM or ATR by siRNA decreases abundance of p53,phosphorylated p53 and p-AKT.(D)Quantitative-PCR determination of the level of ATR or ATM in U20S cells transfected with siRNA to ATR or ATM,respectively.Scramble siRNA(Si-Ctl)was used as control.Data represent the mean±SEM,n=3-4.(E)ATM(KU60019)or ATR(VE-821)inhibitor decreases abundance of p-AKT in U20S cells.U20S cells were treated with indicated concentration of KU60019 or VE-821 for 24 h.(F)The expression of wt-p53,but not mutant p53(p53-s269e)defective of transcription activity,increases the level of p-AKT.(G)PFTa.an inhibitor of p53 transcription activity,suppresses the phosphorylation of AKT.U20S cells were treated with indicated concentration of PFTa for 24 h.

The role of telomere-binding modulators in pluripotent stem cells

Pluripotent stem cells(PSCs)such as embryonic stem cells(ESCs),ESCs derived by somatic cell nuclear transfer(ntESCs),and induced pluripotent stem cells(iPSCs)have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells.In order to maintain their self-renewal and pluripotency,PSCs need to preserve their telomere length and homeostasis.In recent years,increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process.Telomere-associated proteins are not only required for telomere maintenance in both stem cells,their extra-telomeric functions have also been found to be critical as well.Here,we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency.