mTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo.
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.
Department of Cell Biology, Southern Medical University, Guangzhou 510515, China.
Yue
Y
Zhang
Song
S
Xu
Jun
J
Lin
Guangyu
G
Yao
Zelong
Z
Han
Bo
B
Liang
Zhenhong
Z
Zou
Zhenguo
Z
Chen
Qiancheng
Q
Song
Yifan
Y
Dai
Tianming
T
Gao
Anling
A
Liu
Xiaochun
X
Bai
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D047368:Tumor Burden / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D009637:Masoprocol; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases