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Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014.
Biochem Biophys Res Commun. 2014 Jan 10; 443(2):406-12.BB

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+Show Affiliations

Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.Department of General Surgery, The Ninth People's Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai 200011, China.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24309100

Citation

Huo, Hai-zhong, et al. "Dramatic Suppression of Colorectal Cancer Cell Growth By the Dual mTORC1 and mTORC2 Inhibitor AZD-2014." Biochemical and Biophysical Research Communications, vol. 443, no. 2, 2014, pp. 406-12.
Huo HZ, Zhou ZY, Wang B, et al. Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014. Biochem Biophys Res Commun. 2014;443(2):406-12.
Huo, H. Z., Zhou, Z. Y., Wang, B., Qin, J., Liu, W. Y., & Gu, Y. (2014). Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014. Biochemical and Biophysical Research Communications, 443(2), 406-12. https://doi.org/10.1016/j.bbrc.2013.11.099
Huo HZ, et al. Dramatic Suppression of Colorectal Cancer Cell Growth By the Dual mTORC1 and mTORC2 Inhibitor AZD-2014. Biochem Biophys Res Commun. 2014 Jan 10;443(2):406-12. PubMed PMID: 24309100.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014. AU - Huo,Hai-zhong, AU - Zhou,Zhi-yuan, AU - Wang,Bing, AU - Qin,Jian, AU - Liu,Wen-yong, AU - Gu,Yan, Y1 - 2013/12/02/ PY - 2013/11/18/received PY - 2013/11/24/accepted PY - 2013/12/7/entrez PY - 2013/12/7/pubmed PY - 2014/3/13/medline KW - 3-MA KW - 3-methyaldenine KW - 4E-BP1 KW - AZD-2014 KW - Autophagy KW - Colorectal cancer KW - LC3B KW - S6K KW - Signaling KW - eukaryotic initiation factor 4E-binding protein 1 KW - light chain 3B KW - mTOR KW - mTOR complex 1 KW - mTOR complex 2 KW - mTOR complexes KW - mTORC1 KW - mTORC2 KW - mammalian target or rapamycin KW - p70-S6 Kinase 1 SP - 406 EP - 12 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 443 IS - 2 N2 - 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. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/24309100/Dramatic_suppression_of_colorectal_cancer_cell_growth_by_the_dual_mTORC1_and_mTORC2_inhibitor_AZD_2014_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(13)02001-9 DB - PRIME DP - Unbound Medicine ER -