γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death

Abstract

The anticancer effects of γ-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 μmol/L of γ-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. γ-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of γ-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that γ-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.

Synergistic anticancer effects of combined γ-tocotrienol and oridonin treatment is associated with the induction of autophagy

“…Although previous studies have shown that both ctocotrienol and oridonin display anticancer activity and promote autophagy when given alone [7,11,40], the synergistic action of these phytochemicals when used in combination had not previously been shown. Results in the present study confirm and extend previous findings [7,41] and further demonstrate that c-tocotrienol-induced autophagy in both human and mouse mammary cancer cell lines play an important role in mediating the anticancer effects of these phytochemicals.…”

“…The exact mechanism involved in mediating these effects of combined c-tocotrienol and oridonin treatment are presently unknown. However, recent findings suggest that c-tocotrienol-induced endoplasmic reticulum stress-mediated apoptosis and autophagy occurs concurrently and together act to promote human breast cancer cell death [41]. Additional studies are required to determine if this mechanism is also involved in mediating combined c-tocotrienol and oridonin-induced caspase-3 dependent apoptosis in ?SA mammary cancer cells.…”

Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes

“…Our previous work as well as others has shown that ␥ T3 can block NF B activation ( 5-7 ) and stimulate AMPactivated protein kinase (AMPK) and autophagy in a variety of cell types (15)(16)(17)(18). In the present study, we ask whether ␥ T3 represses the NLRP3 infl ammasome and associated infl ammatory processes in type 2 diabetes by modulating NF B, AMPK, and autophagy signaling pathways.…”

δ‐Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells

“…52,53 TTs (specifically γ-and δ-TT) were shown to induce apoptosis by triggering the ER stress branches in cervical cancer, 30 breast cancer 54 and melanoma cells. γ-TT was shown to concurrently trigger ER stress and autophagy in inducing apoptosis in breast cancer cells.…”