Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Pat GulhatiB Mark Evers

Abstract

The mammalian target of rapamycin (mTOR) kinase acts downstream of phosphoinositide 3-kinase/Akt to regulate cellular growth, metabolism, and cytoskeleton. Because approximately 60% of sporadic colorectal cancers (CRC) exhibit high levels of activated Akt, we determined whether downstream mTOR signaling pathway components are overexpressed and activated in CRCs. HCT116, KM20, Caco-2, and SW480 human CRC cells were used to determine the effects of pharmacologic (using rapamycin) or genetic (using RNAi) blockade of mTOR signaling on cell proliferation, apoptosis, cell cycle progression, and subcutaneous growth in vivo. We show that the mTOR complex proteins mTOR, Raptor, and Rictor are overexpressed in CRC. Treatment with rapamycin significantly decreased proliferation of certain CRC cell lines (rapamycin sensitive), whereas other cell lines were resistant to its effects (rapamycin resistant). Transient siRNA-mediated knockdown of the mTORC2 protein, Rictor, significantly decreased proliferation of both rapamycin-sensitive and rapamycin-resistant CRC cells. Stable shRNA-mediated knockdown of both mTORC1 and mTORC2 decreased proliferation, increased apoptosis, and attenuated cell cycle progression in rapamycin-sensitive CRCs. More...Continue Reading

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Citations

Jul 1, 2010·The Journal of Antibiotics·Sung Ryeol ParkYeo Joon Yoon
Dec 24, 2010·The Journal of Biological Chemistry·Jianyu LiuTianyan Gao
Apr 7, 2011·Pigment Cell & Melanoma Research·Lauretta LevatiStefania D'Atri
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Mar 1, 2012·World Journal of Gastroenterology : WJG·Ferenc Sipos, Orsolya Galamb
Apr 26, 2014·World Journal of Gastroenterology : WJG·Xiao-Wen Wang, Yan-Jie Zhang
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May 2, 2014·British Journal of Pharmacology·M MoschettaM R Carratù
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Jan 8, 2013·Cellular Signalling·Alejandro ParralesAna María López-Colomé
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Nov 14, 2012·Biomaterials·Yi-Chun ChenGing-Ho Hsiue
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