Research Paper|Volume 5, Issue 2|pp 111—119

Temporal mTOR inhibition protects Fbxw7-deficient mice from radiation-induced tumor development

Yueyong Liu¹, Yurong Huang¹, Zeran Wang¹, Yong Huang², Xiaohua Li², Alexander Louie², Guangwei Wei^1,³, Jian-Hua Mao¹

¹Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
²Drug Studies Unit, University of California at San Francisco, South San Francisco, CA 94080, USA
³Department of Anatomy, Shandong University School of Medicine, Jinan, Shandong, 250012 China

Received: January 16, 2013Accepted: February 22, 2013Published: February 24, 2013

Copyright: © 2013 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 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.