FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis (Cancer Cell, 2010, 18:472-484)

報告日期: 2011/03/11
報告時間: 16:00/16:50
報告學生: 蘇鈺筑 (英文報告)
講評老師: 蔣輯武

Full Text:

FoxOs enforce a progression checkpoint
to constrain mTORC1-activated renal tumorigenesis
Cancer Cell, 2010, 18:472-484
Speaker: Yu-Chu Su
Commentator: Dr. Chi-Wu Chiang
Date: 2011/3/11 (pm 16:00-16:50)
Place: Room 602
The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and proliferation largely through the increase in protein synthesis. mTORC1 hyperactivation is observed in the majority of human renal cell carcinomas (RCC) samples. However, mTORC1 inhibitor treatment alone might enhance tumorigenesis in mTORC1 hyperactivation-driven tumors by stimulating PI3K-AKT-dependent survival. Therefore, it is necessary to investigate the key downstream effectors of AKT that mediate mTORC1-directed feedback circuit. In mammalian systems, activated AKT regulates FoxO transcription factors. AKT phosphorylation of FoxOs inhibits their transcriptional activity by triggering nuclear exclusion and proteasomal degradation. The role of the FoxOs in tumor suppression has received formal proof from murine studies, but the mechanisms are not well understood.
    To establish FoxO tumor suppression function in the context of mTORC1-mediated renal tumorigenesis.
    By using genetically defined mice and human RCC cell line models, this study establishes that FoxOs play a critical role in an mTORC1-directed negative feedback circuit in the context of renal tumorigenesis. In elucidating the biological mechanisms by which loss of FoxO serves to promote renal cancer development, this study provide evidence that knockdown of FoxO leads to increased Myc expression and enhanced cell proliferation. Finally, this study identified Mxi1 and mir-145 as the key downstream effectors of FoxOs in the regulation of Myc signaling.
    FoxO-mediated block operates via suppression of myc through Mxi-SRα and mir-145, establishing a FoxO-Mxi-SRα/mir-145 axis as a major progression block in renal tumor development.
Rini, B.I., Campbell, S.C., and Escudier, B. (2009). Renal cell carcinoma.
Lancet 373, 1119–1132.