Induction of non-apoptotic programmed cell death by oncogenic RAS in human epithelial cells and its suppression by MYC overexpression.
Induction of non-apoptotic programmed cell death by oncogenic RAS in human epithelial cells and its suppression by MYC overexpression.
复制标题
DOI：
10.1093/carcin/bgx124
复制
发表时间：
2018-02-09
期刊：
影响因子：
4.7
通讯作者：
Kiyono T
中科院分区：
文献类型：
--
作者：
Dendo K;Yugawa T;Nakahara T;Ohno SI;Goshima N;Arakawa H;Kiyono T
在正常人上皮细胞中，致癌RAS诱导与巨胞饮体积累相关的非凋亡PCD，这可以被MYC过表达抑制。这种肿瘤抑制途径可以通过MYC抑制或雷帕霉素给药在携带RAS突变的癌细胞中恢复。RAS基因的致癌性突变在约30%的人类癌症中发现，被认为在癌症发展中起重要作用。然而，致癌RAS也可以诱导小鼠和人正常成纤维细胞的衰老。在一些细胞系中，致癌RAS已被报道诱导非凋亡程序性细胞死亡（PCD）。在这里，我们研究了致癌RAS表达在几种类型的正常人上皮细胞的影响。致癌RAS而不是野生型RAS刺激巨胞饮作用，在细胞质中积累大相透明空泡，随后导致细胞死亡，这与最近提出的新型PCD，methuosis没有区别。RAC1抑制剂抑制巨胞饮体的积累和MYC的过表达，从而减弱致癌RAS诱导的这种积累、细胞周期停滞和细胞死亡。在RAS基因中携带致癌突变的一些癌细胞系中，MYC抑制或雷帕霉素治疗诱导细胞死亡，伴随大胞饮体的积累。这些结果表明，这种类型的非凋亡PCD是一种肿瘤抑制机制，作用于正常人上皮细胞中的致癌RAS突变，这可以通过MYC过表达来克服，从而提高了其诱导可能成为治疗RAS突变的人类癌症的新方法的可能性。
In normal human epithelial cells, oncogenic RAS induces non-apoptotic PCD associated with macropinosome accumulation, which can be inhibited by MYC overexpression. This tumour suppressive pathway could be restored by MYC inhibition or rapamycin administration in cancer cells harbouring RAS mutations. Oncogenic mutations of RAS genes, found in about 30% of human cancers, are considered to play important roles in cancer development. However, oncogenic RAS can also induce senescence in mouse and human normal fibroblasts. In some cell lines, oncogenic RAS has been reported to induce non-apoptotic programed cell death (PCD). Here, we investigated effects of oncogenic RAS expression in several types of normal human epithelial cells. Oncogenic RAS but not wild-type RAS stimulated macropinocytosis with accumulation of large-phase lucent vacuoles in the cytoplasm, subsequently leading to cell death which was indistinguishable from a recently proposed new type of PCD, methuosis. A RAC1 inhibitor suppressed accumulation of macropinosomes and overexpression of MYC attenuated oncogenic RAS-induced such accumulation, cell cycle arrest and cell death. MYC suppression or rapamycin treatment in some cancer cell lines harbouring oncogenic mutations in RAS genes induced cell death with accumulation of macropinosomes. These results suggest that this type of non-apoptotic PCD is a tumour-suppressing mechanism acting against oncogenic RAS mutations in normal human epithelial cells, which can be overcome by MYC overexpression, raising the possibility that its induction might be a novel approach to treatment of RAS-mutated human cancers.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.3
作者：
Amyere, M;Payrastre, B;Courtoy, PJ
通讯作者：
Courtoy, PJ
影响因子：
56.9
作者：
HERMEKING, H;EICK, D
通讯作者：
EICK, D
影响因子：
4.8
作者：
Kaul, Apama;Overmeyer, Jean H.;Maltese, William A.
通讯作者：
Maltese, William A.