Abstract
FBXW7 acts as a tumor suppressor in numerous types of human cancers through ubiquitination of different oncoproteins including mTOR. However, how the mutation/loss of Fbxw7 results in tumor development remains largely unknown. Here we report that downregulation of mTOR by radiation is Fbxw7-dependent, and short-term mTOR inhibition by rapamycin after exposure to radiation significantly postpones tumor development in Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice but not in p53 single heterozygous (p53+/-) mice. Tumor latency of rapamycin treated Fbxw7+/-p53+/- mice is remarkably similar to those of p53+/- mice while placebo treatedFbxw7+/-p53+/- mice develop tumor significantly earlier than placebo treated p53+/- mice. Furthermore, we surprisingly find that, although temporal treatment of rapamycin is given at a young age, the inhibition of mTOR activity sustainably remains in tumors. These results indicate that inhibition of mTOR signaling pathway suppresses the contribution of Fbxw7 loss toward tumor development.
Highlights
FBXW7 is one of the most important human tumor suppressor genes, which undergoes deletion and/or mutation in cancers from a wide spectrum of human tissues, such as breast, colon, endometrium, stomach, lung, ovary, pancreas, and prostate [1, 2]
Western blot analysis showed that, at different time points post radiation, there is a decrease in the phosphorylation levels of mTOR (p-mTOR) in HCT116 FBXW7+/+ cells while there is no change in HCT116 FBXW7-/- cells, which is confirmed by downstream the phosphorylation levels of s6 Ribosomal Protein (p-s6rp) (Fig. 1A)
Our results demonstrate that mTOR signaling pathway is inhibited following radiation exposure, which can be explained by that radiation activates p53, in turn p53 transcriptionally upregulates Fbxw7, subsequently Fbxw7 downregulates mTOR through ubiquitination. p53 inhibits mTOR through Fbxw7 and subsequently prevents cellular senescence [23,24,25]
Summary
FBXW7 is one of the most important human tumor suppressor genes, which undergoes deletion and/or mutation in cancers from a wide spectrum of human tissues, such as breast, colon, endometrium, stomach, lung, ovary, pancreas, and prostate [1, 2]. The overall frequency of point mutation of FBXW7 in human cancers is about 6% [3]. Haploinsufficient loss of Fbxw is observed in most lymphomas in the mouse model, even those arising from Fbxw7/p53 double heterozygous mice [17]. Similar observations of heterozygous mutations were subsequently made in human tumors [18]. These findings suggest that loss of only one copy of the gene can generate a substantial biological impact
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