Lang Sven A, Hackl Christina, Moser Christian, Fichtner-Feigl Stefan, Koehl Gudrun E, Schlitt Hans J, Geissler Edward K, Stoeltzing Oliver
Department of Surgery, University Medical Center Regensburg, Regensburg, Germany.
Biochim Biophys Acta. 2010 Apr;1803(4):435-42. doi: 10.1016/j.bbamcr.2010.01.009. Epub 2010 Jan 28.
Inhibition of mTORC1 with the mTOR inhibitor rapamycin may lead to an induction of Akt phosphorylation in cancer cells via mTORC2 activation. Using gastric and pancreatic cancer cells, we further investigated this paradoxical signaling response and found that rapamycin additionally up-regulates both IGF-IR and Her2 expression. Using RNAi for down-regulating RICTOR, this induction of receptor kinase expression was identified to be mediated via an mTORC2-induced Akt activation. Moreover, mTORC2 inhibition reduced the phosphorylation of GSK-3 and NF-kappaB, and significantly impaired cancer cell motility. In conclusion, inhibition of mTORC2 may abrogate unfavorable signaling effects of mTOR inhibitors, hence providing a novel rationale for therapy.
用mTOR抑制剂雷帕霉素抑制mTORC1可能会通过激活mTORC2导致癌细胞中Akt磷酸化。我们使用胃癌和胰腺癌细胞进一步研究了这种矛盾的信号反应，发现雷帕霉素还会额外上调IGF-IR和Her2的表达。使用RNA干扰下调RICTOR，发现这种受体激酶表达的诱导是通过mTORC2诱导的Akt激活介导的。此外，抑制mTORC2会降低GSK-3和NF-κB的磷酸化，并显著损害癌细胞的运动能力。总之，抑制mTORC2可能会消除mTOR抑制剂的不良信号作用，从而为治疗提供新的理论依据。
