authors: Hu Z., Wang Y., Huang F., Chen R., Li C., Wang F., Goto J., Kwiatkowski DJ., Wdzieczak-Bakala J., Tu P., Liu J., Zha X., Zhang H.

J Biol Chem; 2015 Oct 16;290(42): 25756-65. doi: 10.1074/jbc.M115.665208.

Abstract

Frequent alteration of upstream proto-oncogenes and tumor suppressor genes activates mechanistictarget of rapamycin(mTOR) and causes cancer. However, the downstream effectors of mTOR remain largely elusive. Here we report that brain-expressedX-linked2 (BEX2) is a novel downstream effector of mTOR. Elevated BEX2 in Tsc2(-/-) mouse embryonic fibroblasts, Pten(-/-) mouse embryonic fibroblasts, Tsc2-deficient rat uterine leiomyoma cells, and brains of neuronal specific Tsc1 knock-out mice were abolished by mTOR inhibitor rapamycin. Furthermore, BEX2 was also increased in the liver of a hepatic specific Pten knock-out mouse and the kidneys of Tsc2 heterozygous deletion mice, and a patient with tuberous sclerosis complex (TSC). mTOR up-regulation of BEX2 was mediated in parallel by both STAT3 and NF-κB. BEX2 was involved in mTOR up-regulation of VEGF production and angiogenesis. Depletion of BEX2 blunted the tumorigenesis of cells with activated mTOR. Therefore, enhanced STAT3/NF-κB-BEX2-VEGF signaling pathway contributes to hyperactivemTOR-induced tumorigenesis. BEX2 may be targeted for the treatment of the cancers with aberrantly activated mTOR signaling pathway.