AKT/mTOR signaling in liver tumor development
Xin Chen, PhD
School of Pharmacy,University of California
Biography：Dr. Xin Chen graduated from Beijing Medical University in 1992. She obtained her Ph.D degree from Program in Biological and Biomedical Sciences, Harvard University in 1997. Her graduate work focused on TGF-beta signaling in early Xenopus development. From 1998 to 2002, she did her postdoctal training with Dr. Patrick Brown at Stanford University, and her research focus was the genomic analysis of human hepatocellular carcinoma. Since 2003, she has been a faculty member of the Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF). Currently, her lab studies the molecular genetics and signaling pathways during hepatic carcinogenesis using both in vitro and vivo approaches.
Abstract：Activation of PI3K/AKT/mTOR cascade is frequently observed in human of human hepatocellular carcinoma (HCC). Concomitant expression of activated forms of AKT and Ras oncogenes (AKT/Ras) in mouse liver leads to rapid tumor formation through activation of mTORC1 pathway. mTORC1 functions by regulating p70S6K/RPS6 and 4EBP1/eIF4E cascades. Here we show that inhibition of RPS6 via Rapamycin effectively suppressed, whereas blockade of the 4EBP1/eIF4E cascade by 4EBP1A4, an unphosphorylatable form of 4EBP1, significantly delayed, AKT/Ras induced hepatocarcinogenesis. Combined treatment with Rapamycin and 4EBP1A4 completely inhibited AKT/Ras hepatocarcinogenesis. This strong anti-neoplastic effect was successfully recapitulated by ablating Raptor, the major subunit of mTORC1, in AKT/Ras-overexpressing livers. Mechanistically, we identified the ENTPD5/AK1/CMPK1 axis and the mitochondrial biogenesis pathway as targets of the 4EBP1/eIF4E cascade in mouse liver tumors as well as in human HCC cell lines and tissues. In summary, the mTORC1 effectors, RPS6 and eIF4E, play distinct roles and are both necessary for AKT/Ras hepatocarcinogenesis. These new findings might open the way for innovative therapies against human hepatocellular carcinoma.
Time: Mar.31th.2015,16:00
Venue: New Biology Buliding,Room 143
Host: Prof.Ligong Chen
举办单位：生命科学联合中心
