title: Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014.
abstract: Colorectal cancer is a major contributor of cancer-related mortality. The mammalian target or rapamycin (mTOR) signaling is frequently hyper-activated in colorectal cancers, promoting cancer progression and chemo-resistance. In the current study, we investigated the anti-colorectal cancer effect of a novel mTOR complex 1 (mTORC1) and mTORC2 dual inhibitor: AZD-2014. In cultured colorectal cancer cell lines, AZD-2014 significantly inhibited cancer cell growth without inducing significant cell apoptosis. AZD-2014 blocked activation of both mTORC1 (S6K and S6 phosphorylation) and mTORC2 (Akt Ser 473 phosphorylation), and activated autophagy in colorectal cancer cells. Meanwhile, autophagy inhibition by 3-methyaldenine (3-MA) and hydroxychloroquine, as well as by siRNA knocking down of Beclin-1 or ATG-7, inhibited AZD-2014-induced cytotoxicity, while the apoptosis inhibitor had no rescue effect. In vivo, AZD-2014 oral administration significantly inhibited the growth of HT-29 cell xenograft in SCID mice, and the mice survival was dramatically improved. At the same time, in xenografted tumors administrated with AZD-2014, the activation of mTORC1 and mTORC2 were largely inhibited, and autophagic markers were significantly increased. Thus, AZD-2014 inhibits colorectal cancer cell growth both in vivo and in vitro. Our results suggest that AZD-2014 may be further investigated for colorectal cancer therapy in clinical trials.
authors.affiliation: Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.
authors.forename: Hai-zhong
authors.initials: HZ
authors.lastname: Huo
authors.affiliation: Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.
authors.forename: Zhi-yuan
authors.initials: ZY
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.
authors.forename: Wen-yong
authors.initials: WY
authors.lastname: Liu
authors.affiliation: Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China. Electronic address: drguyan@hotmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: 3-MA; 3-methyaldenine; 4E-BP1; AZD-2014; Autophagy; Colorectal cancer; LC3B; S6K; Signaling; eukaryotic initiation factor 4E-binding protein 1; light chain 3B; mTOR; mTOR complex 1; mTOR complex 2; mTOR complexes; mTORC1; mTORC2; mammalian target or rapamycin; p70-S6 Kinase 1