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.