Research Paper Volume 5, Issue 2 pp 111—119
Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development
- 1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
- 2 Drug Studies Unit, University of California at San Francisco, South San Francisco, CA 94080, USA
- 3 Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong, 250012 China
received: January 16, 2013 ; accepted: February 22, 2013 ; published: February 24, 2013 ;https://doi.org/10.18632/aging.100535
How to Cite
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 treated Fbxw7+/−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.