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Vitamin E succinate induces apoptosis via the PI3K/AKT signaling pathways in EC109 esophageal cancer cells.

Yang P, Zhao J, Hou L, Yang L, Wu K, Zhang L - Mol Med Rep (2016)

Bottom Line: Furthermore, VES downregulated constitutively active basal levels of phosphorylated (p)‑serine‑threonine kinase AKT (AKT) and p‑mammalian target of rapamycin (mTOR), and decreased the phosphorylation of AKT substrates Bcl‑2‑associated death receptor and caspase‑9, in addition to mTOR effectors, ribosomal protein S6 kinase β1 and eIF4E‑binding protein 1.Phosphoinositide‑3‑kinase (PI3K) inhibitor, LY294002 suppressed p‑AKT and p‑mTOR, indicating PI3K is a common upstream mediator.Furthermore, the current study suggests that VES may be useful in a combinational therapeutic strategy employing an mTOR inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.

ABSTRACT
Esophageal cancer is the fourth most common gastrointestinal cancer, it generally has a poor prognosis and novel strategies are required for prevention and treatment. Vitamin E succinate (VES) is a potential chemical agent for cancer prevention and therapy as it exerts anti‑tumor effects in a variety of cancers. However, the role of VES in tumorigenesis and progression of cancer remains to be elucidated. The present study aimed to determine the effects of VES in regulating the survival and apoptosis of human esophageal cancer cells. EC109 human esophageal cancer cells were used to investigate the anti‑proliferative effects of VES. The MTT and Annexin V‑fluorescein isothiocyanate/propidium iodide assays demonstrated that VES inhibited cell proliferation and induced apoptosis in esophageal cancer cells. Furthermore, VES downregulated constitutively active basal levels of phosphorylated (p)‑serine‑threonine kinase AKT (AKT) and p‑mammalian target of rapamycin (mTOR), and decreased the phosphorylation of AKT substrates Bcl‑2‑associated death receptor and caspase‑9, in addition to mTOR effectors, ribosomal protein S6 kinase β1 and eIF4E‑binding protein 1. Phosphoinositide‑3‑kinase (PI3K) inhibitor, LY294002 suppressed p‑AKT and p‑mTOR, indicating PI3K is a common upstream mediator. The apoptosis induced by VES was increased by inhibition of AKT or mTOR with their respective inhibitor in esophageal cancer cells. The results of the present study suggested that VES targeted the PI3K/AKT signaling pathways and induced apoptosis in esophageal cancer cells. Furthermore, the current study suggests that VES may be useful in a combinational therapeutic strategy employing an mTOR inhibitor.

No MeSH data available.


Related in: MedlinePlus

Inhibitors of PI3K, AKT and mTOR enhance VES-induced apoptosis. (A) EC109 cells were cultured with 15 µM VES, plus 2 µM PI3KI, LY294002, 10 µM AKTI, triciribine, and 50 nM mTORI, rapamycin for 24 h. Apoptosis was determined by fluorescence-activated cell sorting analysis. (B and C) Protein levels of p-AKT (Ser473) and p-mTOR (Ser2448), in addition to expression levels of total AKT and mTOR were determined by western blot analyses in EC109 cells treated with the three inhibitors and VES. (D) EC109 cells were treated with 50 nM mTORI rapamycin and 15 µM VES for 24 h. Protein expression levels of p-AKT (Ser473), AKT and GAPDH were determined by western blot analyses. Protein expression levels were quantified and presented as the mean ± standard error of the mean. *P<0.05 vs. ctrl group. PI3K, phosphoinositide-3-kinase; AKT, serine-threonine kinase AKT; mTOR, mammalian target of rapamycin; VES, vitamin E succinate; p, phosphorylated; PI3KI, PI3K inhibitor; AKTI, AKT inhibitor; mTORI, mTOR inhibitor; Ctrl, control.
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f5-mmr-14-02-1531: Inhibitors of PI3K, AKT and mTOR enhance VES-induced apoptosis. (A) EC109 cells were cultured with 15 µM VES, plus 2 µM PI3KI, LY294002, 10 µM AKTI, triciribine, and 50 nM mTORI, rapamycin for 24 h. Apoptosis was determined by fluorescence-activated cell sorting analysis. (B and C) Protein levels of p-AKT (Ser473) and p-mTOR (Ser2448), in addition to expression levels of total AKT and mTOR were determined by western blot analyses in EC109 cells treated with the three inhibitors and VES. (D) EC109 cells were treated with 50 nM mTORI rapamycin and 15 µM VES for 24 h. Protein expression levels of p-AKT (Ser473), AKT and GAPDH were determined by western blot analyses. Protein expression levels were quantified and presented as the mean ± standard error of the mean. *P<0.05 vs. ctrl group. PI3K, phosphoinositide-3-kinase; AKT, serine-threonine kinase AKT; mTOR, mammalian target of rapamycin; VES, vitamin E succinate; p, phosphorylated; PI3KI, PI3K inhibitor; AKTI, AKT inhibitor; mTORI, mTOR inhibitor; Ctrl, control.

Mentions: To investigate the effects of inhibition of members of PI3K signaling pathway on VES-induced apoptosis, EC109 cells were treated with 15 µM VES plus 2 µM LY294002, 10 µM AKT inhibitor triciribine, and 50 nM mTOR inhibitor rapamycin for 24 h. Single treatments with VES or inhibitors induced apoptosis, whereas VES combined with each inhibitor individually markedly increased the induction of apoptosis compared with single treatments (Fig. 5A). VES and the PI3K inhibitor decreased the expression levels of p-AKT and p-mTOR, and the combination of VES + PI3K inhibitor synergistically decreased expression levels of p-AKT and p-mTOR in comparison with individual treatments or the control (Fig. 5B). AKT and mTOR inhibitors increased VES downregulation of p-AKT and p-mTOR, respectively (Fig. 5C). These data indicate that VES inhibited the activation of AKT and mTOR, and may function with the inhibitors of AKT and mTOR to promote esophageal cancer cell apoptosis.


Vitamin E succinate induces apoptosis via the PI3K/AKT signaling pathways in EC109 esophageal cancer cells.

Yang P, Zhao J, Hou L, Yang L, Wu K, Zhang L - Mol Med Rep (2016)

Inhibitors of PI3K, AKT and mTOR enhance VES-induced apoptosis. (A) EC109 cells were cultured with 15 µM VES, plus 2 µM PI3KI, LY294002, 10 µM AKTI, triciribine, and 50 nM mTORI, rapamycin for 24 h. Apoptosis was determined by fluorescence-activated cell sorting analysis. (B and C) Protein levels of p-AKT (Ser473) and p-mTOR (Ser2448), in addition to expression levels of total AKT and mTOR were determined by western blot analyses in EC109 cells treated with the three inhibitors and VES. (D) EC109 cells were treated with 50 nM mTORI rapamycin and 15 µM VES for 24 h. Protein expression levels of p-AKT (Ser473), AKT and GAPDH were determined by western blot analyses. Protein expression levels were quantified and presented as the mean ± standard error of the mean. *P<0.05 vs. ctrl group. PI3K, phosphoinositide-3-kinase; AKT, serine-threonine kinase AKT; mTOR, mammalian target of rapamycin; VES, vitamin E succinate; p, phosphorylated; PI3KI, PI3K inhibitor; AKTI, AKT inhibitor; mTORI, mTOR inhibitor; Ctrl, control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940098&req=5

f5-mmr-14-02-1531: Inhibitors of PI3K, AKT and mTOR enhance VES-induced apoptosis. (A) EC109 cells were cultured with 15 µM VES, plus 2 µM PI3KI, LY294002, 10 µM AKTI, triciribine, and 50 nM mTORI, rapamycin for 24 h. Apoptosis was determined by fluorescence-activated cell sorting analysis. (B and C) Protein levels of p-AKT (Ser473) and p-mTOR (Ser2448), in addition to expression levels of total AKT and mTOR were determined by western blot analyses in EC109 cells treated with the three inhibitors and VES. (D) EC109 cells were treated with 50 nM mTORI rapamycin and 15 µM VES for 24 h. Protein expression levels of p-AKT (Ser473), AKT and GAPDH were determined by western blot analyses. Protein expression levels were quantified and presented as the mean ± standard error of the mean. *P<0.05 vs. ctrl group. PI3K, phosphoinositide-3-kinase; AKT, serine-threonine kinase AKT; mTOR, mammalian target of rapamycin; VES, vitamin E succinate; p, phosphorylated; PI3KI, PI3K inhibitor; AKTI, AKT inhibitor; mTORI, mTOR inhibitor; Ctrl, control.
Mentions: To investigate the effects of inhibition of members of PI3K signaling pathway on VES-induced apoptosis, EC109 cells were treated with 15 µM VES plus 2 µM LY294002, 10 µM AKT inhibitor triciribine, and 50 nM mTOR inhibitor rapamycin for 24 h. Single treatments with VES or inhibitors induced apoptosis, whereas VES combined with each inhibitor individually markedly increased the induction of apoptosis compared with single treatments (Fig. 5A). VES and the PI3K inhibitor decreased the expression levels of p-AKT and p-mTOR, and the combination of VES + PI3K inhibitor synergistically decreased expression levels of p-AKT and p-mTOR in comparison with individual treatments or the control (Fig. 5B). AKT and mTOR inhibitors increased VES downregulation of p-AKT and p-mTOR, respectively (Fig. 5C). These data indicate that VES inhibited the activation of AKT and mTOR, and may function with the inhibitors of AKT and mTOR to promote esophageal cancer cell apoptosis.

Bottom Line: Furthermore, VES downregulated constitutively active basal levels of phosphorylated (p)‑serine‑threonine kinase AKT (AKT) and p‑mammalian target of rapamycin (mTOR), and decreased the phosphorylation of AKT substrates Bcl‑2‑associated death receptor and caspase‑9, in addition to mTOR effectors, ribosomal protein S6 kinase β1 and eIF4E‑binding protein 1.Phosphoinositide‑3‑kinase (PI3K) inhibitor, LY294002 suppressed p‑AKT and p‑mTOR, indicating PI3K is a common upstream mediator.Furthermore, the current study suggests that VES may be useful in a combinational therapeutic strategy employing an mTOR inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.

ABSTRACT
Esophageal cancer is the fourth most common gastrointestinal cancer, it generally has a poor prognosis and novel strategies are required for prevention and treatment. Vitamin E succinate (VES) is a potential chemical agent for cancer prevention and therapy as it exerts anti‑tumor effects in a variety of cancers. However, the role of VES in tumorigenesis and progression of cancer remains to be elucidated. The present study aimed to determine the effects of VES in regulating the survival and apoptosis of human esophageal cancer cells. EC109 human esophageal cancer cells were used to investigate the anti‑proliferative effects of VES. The MTT and Annexin V‑fluorescein isothiocyanate/propidium iodide assays demonstrated that VES inhibited cell proliferation and induced apoptosis in esophageal cancer cells. Furthermore, VES downregulated constitutively active basal levels of phosphorylated (p)‑serine‑threonine kinase AKT (AKT) and p‑mammalian target of rapamycin (mTOR), and decreased the phosphorylation of AKT substrates Bcl‑2‑associated death receptor and caspase‑9, in addition to mTOR effectors, ribosomal protein S6 kinase β1 and eIF4E‑binding protein 1. Phosphoinositide‑3‑kinase (PI3K) inhibitor, LY294002 suppressed p‑AKT and p‑mTOR, indicating PI3K is a common upstream mediator. The apoptosis induced by VES was increased by inhibition of AKT or mTOR with their respective inhibitor in esophageal cancer cells. The results of the present study suggested that VES targeted the PI3K/AKT signaling pathways and induced apoptosis in esophageal cancer cells. Furthermore, the current study suggests that VES may be useful in a combinational therapeutic strategy employing an mTOR inhibitor.

No MeSH data available.


Related in: MedlinePlus