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mTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo.
Breast Cancer Res Treat. 2012 Nov; 136(2):379-88.BC

Abstract

Nordihydroguaiaretic acid (NDGA) is a natural phenolic compound isolated from the creosote bush Larrea divaricata, which has anti-tumor activities both in vitro and in vivo. Its analogs are in clinical development for use in refractory solid tumors. But the mechanisms underlying the anti-cancer effect of NDGA are not fully understood. In this study, we identified mammalian target of rapamycin complex 1 (mTORC1) as a target of NDGA both in cultured breast cancer cells and in xenograft models. NDGA effectively inhibited basal level of mTORC1 but not mTORC2 activity in breast cancer cell lines. NDGA also suppressed mTORC1 downstream signaling such as expression of cyclin D1, hypoxia-inducible factor-α and VEGF, and prevented proliferation in breast cancer cells. Although NDGA stimulated AMP-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2) signaling, which negatively regulates mTORC1, AMPK and TSC2 deletion could not diminish the inhibition of mTORC1 by NDGA. Subsequent studies revealed that NDGA may also direct target mTORC1 complex because NDGA suppressed amino acids- and insulin-stimulated mTORC1 and acted like rapamycin to disrupt mTOR-Raptor interaction. Most importantly, NDGA repressed breast tumor growth and targeted mTORC1 and its downstream signaling in xenograft models. Together our data provide a novel mechanism for NDGA activity which could help explain its anti-cancer activity. Disruption of mTOR-Raptor complex and activation of AMPK/TSC signaling may contribute to inhibitory effects of NDGA against mTORC1. Our data also raise the possibility that NDGA, as an mTORC1 inhibitor, may have a broad spectrum of action on breast cancers.

Authors+Show Affiliations

Department of Cell Biology, Southern Medical University, Guangzhou 510515, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23053656

Citation

Zhang, Yue, et al. "MTORC1 Is a Target of Nordihydroguaiaretic Acid to Prevent Breast Tumor Growth in Vitro and in Vivo." Breast Cancer Research and Treatment, vol. 136, no. 2, 2012, pp. 379-88.
Zhang Y, Xu S, Lin J, et al. MTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo. Breast Cancer Res Treat. 2012;136(2):379-88.
Zhang, Y., Xu, S., Lin, J., Yao, G., Han, Z., Liang, B., Zou, Z., Chen, Z., Song, Q., Dai, Y., Gao, T., Liu, A., & Bai, X. (2012). MTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo. Breast Cancer Research and Treatment, 136(2), 379-88. https://doi.org/10.1007/s10549-012-2270-7
Zhang Y, et al. MTORC1 Is a Target of Nordihydroguaiaretic Acid to Prevent Breast Tumor Growth in Vitro and in Vivo. Breast Cancer Res Treat. 2012;136(2):379-88. PubMed PMID: 23053656.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - mTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo. AU - Zhang,Yue, AU - Xu,Song, AU - Lin,Jun, AU - Yao,Guangyu, AU - Han,Zelong, AU - Liang,Bo, AU - Zou,Zhenhong, AU - Chen,Zhenguo, AU - Song,Qiancheng, AU - Dai,Yifan, AU - Gao,Tianming, AU - Liu,Anling, AU - Bai,Xiaochun, Y1 - 2012/09/29/ PY - 2012/05/23/received PY - 2012/09/20/accepted PY - 2012/10/12/entrez PY - 2012/10/12/pubmed PY - 2013/6/15/medline SP - 379 EP - 88 JF - Breast cancer research and treatment JO - Breast Cancer Res Treat VL - 136 IS - 2 N2 - Nordihydroguaiaretic acid (NDGA) is a natural phenolic compound isolated from the creosote bush Larrea divaricata, which has anti-tumor activities both in vitro and in vivo. Its analogs are in clinical development for use in refractory solid tumors. But the mechanisms underlying the anti-cancer effect of NDGA are not fully understood. In this study, we identified mammalian target of rapamycin complex 1 (mTORC1) as a target of NDGA both in cultured breast cancer cells and in xenograft models. NDGA effectively inhibited basal level of mTORC1 but not mTORC2 activity in breast cancer cell lines. NDGA also suppressed mTORC1 downstream signaling such as expression of cyclin D1, hypoxia-inducible factor-α and VEGF, and prevented proliferation in breast cancer cells. Although NDGA stimulated AMP-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2) signaling, which negatively regulates mTORC1, AMPK and TSC2 deletion could not diminish the inhibition of mTORC1 by NDGA. Subsequent studies revealed that NDGA may also direct target mTORC1 complex because NDGA suppressed amino acids- and insulin-stimulated mTORC1 and acted like rapamycin to disrupt mTOR-Raptor interaction. Most importantly, NDGA repressed breast tumor growth and targeted mTORC1 and its downstream signaling in xenograft models. Together our data provide a novel mechanism for NDGA activity which could help explain its anti-cancer activity. Disruption of mTOR-Raptor complex and activation of AMPK/TSC signaling may contribute to inhibitory effects of NDGA against mTORC1. Our data also raise the possibility that NDGA, as an mTORC1 inhibitor, may have a broad spectrum of action on breast cancers. SN - 1573-7217 UR - https://www.unboundmedicine.com/medline/citation/23053656/mTORC1_is_a_target_of_nordihydroguaiaretic_acid_to_prevent_breast_tumor_growth_in_vitro_and_in_vivo_ L2 - https://doi.org/10.1007/s10549-012-2270-7 DB - PRIME DP - Unbound Medicine ER -