Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling

Abstract

Tocotrienols are naturally occurring forms of vitamin E based on their structural similarity. This study focused on investigating anticancer effects of tocotrienols and the mechanisms of apoptosis induction by tocotrienols in vivo and in vitro. Dietary delivery of γ-tocotrienol (γ-T3) suppressed tumor growth in a syngeneic implantation mouse mammary cancer model by inhibiting cell proliferation and inducing apoptosis. In cell culture studies, γ-T3 inhibited colony formation of a mouse mammary cancer cell line and human breast cancer cell lines. The anti-proliferative effects of tocotrienols were highly correlated with an increase in apoptosis based on Annexin V assessment. Treatment of human MDA-MB-231 and MCF-7 cells with γ-T3 induced cleavages of PARP as well as caspase-8, -9, and -3. Additional analyses showed that γ-T3 activated c-Jun NH(2)-terminal kinase (JNK) and p38 MAPK, and upregulated death receptor 5 (DR5) and C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress marker. Silencing either JNK or p38 MAPK reduced the increase in DR5 and CHOP and partially blocked γ-T3-induced apoptosis. Both DR5 and CHOP upregulation were required for γ-T3-induced apoptosis, and DR5 was transcriptionally regulated by CHOP after γ-T3 treatment. Moreover, γ-T3 increased the level of other ER-stress markers. Taken together, these results suggest that upregulation of DR5 by γ-T3 treatment is dependent on JNK and p38 MAPK activation which is mediated by ER-stress.

Tocotrienols fight cancer by targeting multiple cell signaling pathways

“…We also discovered that tocotrienol induced DR expression in a non-cell-type-specific fashion that is mediated through reactive oxygen species/ extracellular signal-regulated kinase/p53. Similarly, Park et al (2010) observed that tocotrienol induces apoptosis in breast cancer cell lines via an endoplasmic reticulum stressdependent increase in extrinsic death receptor signaling. However, they found that DR5 induction by tocotrienol was transcriptionally regulated by C/EBP homologous protein.…”

“…Park et al (2010) Suppressed preneoplastic mammary epithelial cell proliferation Sylvester et al (2002) Exhibited synergism with erlotinib/gefitinib in suppressing cell proliferation Bachawal et al (2010) Inhibited cell growth irrespective of estrogen receptor status Nesaretnam et al (1998) Exhibited antiproliferation and induced apoptosis by DNA fragmentation McIntyre et al (2000a), McIntyre et al (2000b), Comitato et al (2009) Induced apoptosis in tumor cells through endoplasmic reticulum stress Park et al (2010) Induced apoptosis through TGF-b/Fas/JNK-signaling pathway Shun et al (2004) Reduced PI3K/PDK-1/Akt signaling Sylvester et al (2005) Inhibited cell proliferation and induced apoptosis Shah and Sylvester (2004), Shah and Sylvester (2005b), Sylvester and Shah (2005b), Samant et al (2010) Induced apoptosis through activation of caspases Shah et al (2003), Sylvester and Shah (2005a) Suppressed cell proliferation and down-regulated Bcl-2 and cyclin D1 Hsieh and Wu (2008) Inhibited ER-negative and ER-positive cell proliferation Guthrie et al (1997), Nesaretnam et al (1995) Inhibited proliferation by arresting cell cycle progression Samant et al (2010), Wali et al (2009a) Inhibited tumor cell growth by suppressing HMGR activity Wali et al (2009b) Induced apoptosis through mitochondria-mediated death pathway Takahashi and Loo (2004) Inhibited proliferation through down-regulation of Id1 protein Reduced cell viability and induced apoptosis via the mitochondrial pathway Pierpaoli et al …”

“…However, they found that DR5 induction by tocotrienol was transcriptionally regulated by C/EBP homologous protein. These researchers concluded that up-regulation of DR5 by c-tocotrienol treatment is dependent on the activation of c-jun N-terminal kinase and p38 mitogen-activated protein kinase and that the activation is mediated by endoplasmic reticulum stress (Park et al 2010). …”

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

“…Drug resistance is a major clinical limitation for the successful management of breast cancers (42)(43)(44)(45). In the present study, we investigated the mechanisms of TAM-induced apoptosis and drug resistance using MCF-7 cells and its multidrug-resistant variant, MCF-7/ADR cells.…”

Tocotrienol Vitamin E Protects against Preclinical Canine Ischemic Stroke by Inducing Arteriogenesis

“…A growing body of studies support that different members of the natural vitamin E family may have unique biological properties relevant to health and disease (Aggarwal et al, 2010). For example, anti-tumorigenic properties of g-tocotrienol, not shared by a-tocopherol, have been described in both breast (Park et al, 2010) and prostate (Kumar et al, 2006) cancer. Furthermore, tocotrienol transport to tissue, including brain, has been reported in the absence of tocopherol transfer protein (TTP), the transport system with high affinity for a-tocopherol (Khanna et al, 2005a).…”