γ-Tocotrienol Reversal of Epithelial-to-Mesenchymal Transition in Human Breast Cancer Cells is Mediated through a Suppression of Canonical Wnt and Hedgehog Signaling

Abstract

γ-Tocotrienol, a natural isoform within the vitamin E family of compounds, displays potent antiproliferative, apoptotic and reversal of epithelial-to-mesenchymal transition (EMT) activity against breast cancer using treatment doses that have little or no effect on normal cell viability. EMT is a route by which epithelial cells undergo various biochemical alterations leading to the acquisition of mesenchymal traits. Several aberrant signaling pathways are involved in EMT-dependent cancer metastasis. Specifically, dysregulation of the canonical Wnt and Hedgehog pathways are intimately involved in promoting breast cancer EMT and metastasis. Therefore, studies were conducted to examine effects of γ-tocotrienol on Wnt and Hedgehog signaling. Results from these studies demonstrate that γ-tocotrienol significantly inhibits canonical Wnt and Hedgehog signaling by inhibiting receptors, co-receptors and ligand expression, as well as inhibiting expression of cytosolic and nuclear signaling proteins within these pathways. Additional studies showed that γ-tocotrienol treatment increased the expression of negative regulators of both the Wnt and Hedgehog pathways. These findings demonstrate that γ-tocotrienol reversal of EMT is mediated, at least in part, through the inhibition of canonical Wnt and Hedgehog signaling, and strongly suggest that this form of vitamin E may provide significant benefit in the prevention and treatment of metastatic breast cancer.

Revisiting the therapeutic potential of tocotrienol

“…134 Delta-tocotrienol has further produced anti-metastasis ability in pancreatic tumors by Gamma-tocotrienol further demonstrated anti-metastasis effects in breast tissue by inhibiting EMT through the canonical Wnt signaling mechanism. 97 Interestingly, most of the in vitro studies that were conducted were corroborated with in vivo research that has validated the anti-metastatic effects of tocotrienols in malignant tumors. A plethora of such studies are on record and a handful is mentioned here, that include cell lines from colorectal, prostate, cervical, melanoma, neuroblastoma, and ovarian cancers.…”

“…96 Thus, gamma-tocotrienol treatment promoted the expression of epithelial markers such as E-cadherin and gammacatenin, while mesenchymal markers, alpha-smooth muscle-actin, and vimentin, were suppressed. 97 Furthermore, the anti-cancer stem cell properties of tocotrienol were linked to its potential for reversing EMT, that simultaneously hedged against disease recurrence. 97 In a murine model of colitis-associated colorectal cancer (CAC), treatment with delta-tocotrienol and its metabolite, delta-tocotrienol 13 carboxychromanol together, have displayed a role in modulating the gut microbiome composition but not richness.…”

“…97 Furthermore, the anti-cancer stem cell properties of tocotrienol were linked to its potential for reversing EMT, that simultaneously hedged against disease recurrence. 97 In a murine model of colitis-associated colorectal cancer (CAC), treatment with delta-tocotrienol and its metabolite, delta-tocotrienol 13 carboxychromanol together, have displayed a role in modulating the gut microbiome composition but not richness. 98 CAC was induced in mice by jointly administered azoxymethane and dextran sulfate sodium (DSS) in the diet that was followed by treatment with a delta-tocotrienol mixture that could prevent the multiplicity of large adenomas in the colon.…”

“…Thus, gamma‐tocotrienol treatment promoted the expression of epithelial markers such as E‐cadherin and gamma‐catenin, while mesenchymal markers, alpha‐smooth muscle‐actin, and vimentin, were suppressed 97 . Furthermore, the anti‐cancer stem cell properties of tocotrienol were linked to its potential for reversing EMT, that simultaneously hedged against disease recurrence 97 …”

Potensi Tocotrienol Sebagai Terapi Pada Kanker Payudara Dengan Positif Estrogen

“…Isomer γ-T3 dan δ-T3 telah dilaporkan memiliki efek poten sebagai antikanker. 15,16 Beberapa studi mengenai agen antikanker menunjukkan bahwa γ-T3 dan δ-T3 memiliki aktifitas antikanker yang lebih poten daripada isomer lain pada tocotrienol. 15,16,17 Meskipun, T3 masih dalam tahap evaluasi sebagai agen kemopreventif dalam skala klinis akan tetapi T3 telah banyak diteliti dalam skala besar pada hewan coba.…”