Endoplasmic reticulum stress mediates γ-tocotrienol-induced apoptosis in mammary tumor cells

Wali, Vikram B.; Bachawal, Sunitha V.; Sylvester, Paul W.

doi:10.1007/s10495-009-0406-y

Cited by 76 publications

(77 citation statements)

References 54 publications

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“…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 …”

Section: Nf-jb and Tocotrienolmentioning

confidence: 99%

Tocotrienols fight cancer by targeting multiple cell signaling pathways

et al. 2011

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Cancer cells are distinguished by several distinct characteristics, such as self-sufficiency in growth signal, resistance to growth inhibition, limitless replicative potential, evasion of apoptosis, sustained angiogenesis, and tissue invasion and metastasis. Tumor cells acquire these properties due to the dysregulation of multiple genes and associated cell signaling pathways, most of which are linked to inflammation. For that reason, rationally designed drugs that target a single gene product are unlikely to be of use in preventing or treating cancer. Moreover, targeted drugs can cause serious and even life-threatening side effects. Therefore, there is an urgent need for safe and effective promiscuous (multitargeted) drugs. ''Mother Nature'' produces numerous such compounds that regulate multiple cell signaling pathways, are cost effective, exhibit low toxicity, and are readily available. One among these is tocotrienol, a member of the vitamin E family, which has exhibited anticancer properties. This review summarizes data from in vitro and in vivo studies of the effects of tocotrienol on nuclear factor-jB, signal transducer and activator of transcription (STAT) 3, death receptors, apoptosis, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hypoxia-inducible factor (HIF) 1, growth factor receptor kinases, and angiogenic pathways.

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Section: Nf-jb and Tocotrienolmentioning

confidence: 99%

Tocotrienols fight cancer by targeting multiple cell signaling pathways

et al. 2011

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“…pared as described previously, in Laemmli buffer. 29,30) Protein concentration in each sample was determined using Bio-Rad protein assay kit (Bio Rad, Hercules, CA, U.S.A.). Equal amounts of protein (30-50 µg/lane) from each sample were then subjected to electrophoresis through 7.5-20% sodium dodecyl sulfate (SDS)-polyacrylamide minigels.…”

Section: Methodsmentioning

confidence: 99%

Anticancer Effects of γ-Tocotrienol Are Associated with a Suppression in Aerobic Glycolysis

Parajuli

Tiwari

Sylvester

2015

Biological & Pharmaceutical Bulletin

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Aerobic glycolysis is an established hallmark of cancer. Neoplastic cells display increased glucose consumption and a corresponding increase in lactate production compared to the normal cells. Aerobic glycolysis is regulated by the phosphatidylinositol-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling pathway, as well as by oncogenic transcription factors such as c-Myc and hypoxia inducible factor 1α (HIF-1α). γ-Tocotrienol is a natural isoform within the vitamin E family of compounds that displays potent antiproliferative and apoptotic activity against a wide range of cancer cell types at treatment doses that have little or no effect on normal cell viability. Studies were conducted to determine the effects of γ-tocotrienol on aerobic glycolysis in mouse SA and human MCF-7 breast cancer cells. Treatment with γ-tocotrienol resulted in a dose-responsive inhibition of both SA and MCF-7 mammary tumor cell growth, and induced a relatively large reduction in glucose utilization, intracellular ATP production and extracellular lactate excretion. These effects were also associated with a large decrease in enzyme expression levels involved in regulating aerobic glycolysis, including hexokinase-II, phosphofructokinase, pyruvate kinase M2, and lactate dehydrogenase A. γ-Tocotrienol treatment was also associated with a corresponding reduction in the levels of phosphorylated (active) Akt, phosphorylated (active) mTOR, and c-Myc, but not HIF-1α or glucose transporter 1 (GLUT-1). In summary, these findings demonstrate that the antiproliferative effects of γ-tocotrienol are mediated, at least in the part, by the concurrent inhibition of Akt/mTOR signaling, c-Myc expression and aerobic glycolysis. Key words γ-tocotrienol; aerobic glycolysis; breast cancer; vitamin E; c-MycNormal differentiated nonproliferating cells metabolize glucose for fuel using glycolysis and oxidative phosphorylation. However, during hypoxic conditions glycolysis and oxidative phosphorylation becomes uncoupled and pyruvate is converted to lactate by anaerobic glycolysis.1,2) In contrast, cancer cells often metabolize glucose to lactate independently of oxygen availability using a process call aerobic glycolysis or the "Warburg effect," and this characteristic is considered to be a hallmark of neoplastic transformation.2-5) Although, aerobic glycolysis is less efficient than oxidative phosphorylation and requires the conversion of large quantities of glucose to lactate for the production of ATP, it provides intermediate precursors for the biosynthesis of macromolecules that are essential for cancer cell proliferation.

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“…Endoplasmic reticulum stress induces both apoptosis 40 and autophagy 41 and occurs in response to many submit your manuscript | www.dovepress.com…”

Section: Effect Of Nucleocytoplasmic Transport Blockade On Endoplasmimentioning

confidence: 99%

Nucleocytoplasmic transport blockage by SV40 peptide-modified gold nanoparticles induces cellular autophagy

Tsai¹,

Hou²,

Wang³

et al. 2012

IJN

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Gold nanoparticles modified with the nuclear localization signal from simian virus 40 large T antigen (GNP-PEG/SV40) accumulate on the cytoplasmic side of the nuclear membrane in HeLa cells. Accumulation of GNP-PEG/SV40 around the nucleus blocks nucleocytoplasmic transport and prevents RNA export and nuclear shuttling of signaling proteins. This long-term blockage of nucleocytoplasmic transport results in cell death. This cell death is not caused by apoptosis or necrosis because caspases 3 and 9 are not activated, and the expression of annexin V/propidium iodide is not enhanced in HeLa cells after treatment. Using transmission electron microscopy, autophagosomes and autolysosomes were seen to appear after 72 hours of treatment with GNP-PEG/SV40. Increasing levels of enhanced green fluorescent protein-microtubule-associated protein 1 light chain 3 (EGFP-LC3)-positive punctate and LC3-II confirmed GNP-PEG/SV40-induced autophagy. In SiHa cells, treatment did not induce accumulation of GNP-PEG/SV40 around the nucleus and autophagy. Treating cells with wheat germ agglutinin, a nuclear pore complex inhibitor, induced autophagy in both HeLa and SiHa cells. GNP-PEG/SV40-induced autophagy plays a role in cell death, not survival, and virus-mediated small hairpin RNA silencing of Beclin-1 attenuates cell death. Taken together, the results indicate that long-term blockade of nucleocytoplasmic transport results in autophagic cell death.

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Endoplasmic reticulum stress mediates γ-tocotrienol-induced apoptosis in mammary tumor cells

Cited by 76 publications

References 54 publications

Tocotrienols fight cancer by targeting multiple cell signaling pathways

Tocotrienols fight cancer by targeting multiple cell signaling pathways

Anticancer Effects of γ-Tocotrienol Are Associated with a Suppression in Aerobic Glycolysis

Nucleocytoplasmic transport blockage by SV40 peptide-modified gold nanoparticles induces cellular autophagy

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