Figure 7

Proposed signaling pathways modulated by α-TEA and TAM in TAMR cells. Based on published data and data presented here, a schematic diagram of the actions of α-TEA, MβCD, and TAM on proapoptotic and prosurvival signaling mediators in TAMR cells is depicted. (a) Proapoptotic pathway affected by α-TEA and α-TEA + TAM: α-TEA triggers DR5 extrinsic death receptor-mediated caspase-8/tBid/Bax/mitochondria/caspase-9-dependent apoptosis and caspase-8-mediated endoplasmic reticulum stress-dependent upregulation of JNK/CHOP/DR5 positive-feedback loop. Combination of α-TEA + TAM enhances these apoptotic pathways via suppression of Akt-mediated c-FLIP. (b) Prosurvival pathways affected by α-TEA, MβCD, and TAM. Both α-TEA and MβCD disrupt cholesterol-rich lipid microdomains, leading to suppression of crosstalk between mER-α and RTKs, reduction of total and phosphoprotein levels of RTKs (HER-1 and HER-2), decreased levels of pAkt and pERK1/2, as well as decreased levels of estrogen receptor-α activity via downregulation of nuclear estrogen receptor-α (nER-α) phosphorylation mediated by Akt and ERK (Ser-118 and Ser-167). Both Akt and ERK mediated downstream prosurvival/antiapoptotic mediators, and nER-α promoted proliferation/survival and inhibited apoptosis. In contrast, TAM stimulates survival signaling in TAMR cells. (c) Prosurvival pathways affected by combination of α-TEA or MβCD + TAM: α-TEA or MβCD + TAM cooperatively act to suppress prosurvival signaling, indicating that either α-TEA or MβCD restores TAM sensitivity by converting the TAM prosurvival (agonistic) actions to antisurvival (antagonistic) actions. c-FLIP, cellular FLICE-inhibitory protein; CHOP, Ccaat-enhancer-binding protein (C/EBP) homologous protein; DR5 (L/S), death receptor 5 long/short; HER-1, epidermal growth factor receptor ErbB-1; HER-2, epidermal growth factor receptor-2 ErbB-2; JNK, c-Jun N-terminal kinase; MCF-7/HER-2, clone 18 MCF-7 cells overexpressing HER-2; MCF-7/TAMR, acquired tamoxifen-resistant MCF-7; mER, membrane estrogen receptor; MβCD, methyl-b-cyclodextrin; nER, nuclear estrogen receptor; pAkt, phosphorylated-Akt; pERK1/2, phosphorylated-extracellular signal-regulated kinases 1 and 2; RTKs, receptor tyrosine kinases; TAM, tamoxifen; TAMR, tamoxifen resistant; tBid, truncated Bid; α-TEA, RRR-α-tocopherol ether-linked acetic acid analogue.