Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells.
gamma-Tocotrienol, a member of the vitamin E family of compounds, induces apoptosis in a variety of cancer cell types. However, previous studies have clearly demonstrated that gamma-tocotrienol-induced apoptosis in neoplastic mouse +SA mammary epithelial cells is not mediated through mitochondrial stress or death receptor apoptotic signaling. Therefore, studies were conducted to determine the role of endoplasmic reticulum (ER) stress in mediating gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells. Treatment with 15-40 microM gamma-tocotrienol induced +SA cell death in a dose-responsive manner, and these effects were associated with a corresponding increase in poly (ADP-ribose) polymerase (PARP)-cleavage and activation of protein kinase-like endoplasmic reticulum kinase/eukaryotic translational initiation factor/activating transcription factor 4 (PERK/eIF2alpha/ATF-4) pathway, a marker of ER stress response. These treatments also caused a large increase in C/EBP homologous protein (CHOP) levels, a key component of ER stress mediated apoptosis that increases expression of tribbles 3 (TRB3). Knockdown of CHOP by specific siRNAs attenuated gamma-tocotrienol-induced PARP-cleavage, CHOP and TRB3 expression. gamma-Tocotrienol treatment also reduced full-length caspase-12 levels, an indication of caspase-12 cleavage and activation. Intracellular levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase, an ER-transmembrane enzyme catalyzing the synthesis of mevalonate, decreased following gamma-tocotrienol treatment, but combined treatment with mevalonate did not reverse gamma-tocotrienol-induced apoptosis, suggesting that a decrease in HMGCoA reductase activity is not required for gamma-tocotrienol induced apoptosis. These results demonstrate that ER stress apoptotic signaling is associated with gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells.
Wali
Vikram B
VB
University of Louisiana at Monroe, LA 71209, USA.
Bachawal
Sunitha V
SV
Sylvester
Paul W
PW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000473:pathology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D018797:Cell Cycle Proteins; D002839:Chromans; C497250:Ddit3 protein, mouse; C474830:TRB3 protein, mouse; D014810:Vitamin E; D051742:Transcription Factor CHOP; C013649:plastochromanol 8; D006903:Hydroxymethylglutaryl CoA Reductases; D011065:Poly(ADP-ribose) Polymerases; C506440:Casp12 protein, mouse; D053454:Caspase 12