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Delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis, by inducing DR5 and causing caspase-mediated HDAC3 cleavage.

Ko H, Jeong MH, Jeon H, Sung GJ, So Y, Kim I, Son J, Lee SW, Yoon HG, Choi KC - Oncotarget (2015)

Bottom Line: TRAIL-induced apoptosis in prostate cancer cells pretreated with delphinidin was dependent on death receptor 5 (DR5) and downstream cleavage of histone deacetylase 3 (HDAC3).In conclusion, delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis by inducing DR5, thus causing caspase-mediated HDAC3 cleavage.Our data reveal a potential way of chemoprevention of prostate cancer by enabling TRAIL-mediated apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Oncology, Cheil General Hospital & Women's Healthcare Center, College of Medicine, Dankook University, Seoul, South Korea.

ABSTRACT
TRAIL can induce apoptosis in some cancer cells and is an immune effector in the surveillance and elimination of developing tumors. Yes, some cancers are resistant to TRAIL. Delphinidin, a polyphenolic compound contained in brightly colored fruits and vegetables, has anti-inflammatory, anti-oxidant, and anti-tumorigenic activities. Here we showed that delphinidin sensitized TRAIL-resistant human prostate cancer cells to undergo apoptosis. Cells treated with delphinidin and TRAIL activated the extrinsic and intrinsic pathways of caspase activation. TRAIL-induced apoptosis in prostate cancer cells pretreated with delphinidin was dependent on death receptor 5 (DR5) and downstream cleavage of histone deacetylase 3 (HDAC3). In conclusion, delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis by inducing DR5, thus causing caspase-mediated HDAC3 cleavage. Our data reveal a potential way of chemoprevention of prostate cancer by enabling TRAIL-mediated apoptosis.

No MeSH data available.


Related in: MedlinePlus

TRAIL and delphinidin activate DR5 expression and intrinsic apoptotic pathway(A) Delphinidin induces DR5 in LNCaP and Du145 cells. LNCaP and Du145 cells were treated for 12 h with different concentration of delphinidin (0, 10, 30, 50 μM), and western blot analysis was performed using antibodies against DR5. (B and C) DR5 and BAX expression is critical for the sensitization of TRAIL-mediated apoptosis. LNCaP cells transfected with the scrambled siRNA, DR5 siRNA, or BAX siRNA were further treated with 30 μM delphinidin and 50 ng/ml TRAIL for 12 h. (B) Western blot analysis demonstrated inhibition of caspase-3 cleavage by knockdown of DR5 or BAX and (C) their corresponding antiapoptotic effects. The apoptotic cell death was determined by MTT assay (left) and TUNEL assay (right) kit as described in Materials and Methods. (D) Co-treatment of delphinidin and TRAIL regulates the expression of various apoptosis-related genes at transcriptional level. LNCaP cells were treated with TRAIL (T, 50 ng/ml) and/or delphinidin (D, 30 μM) for 12 h. The expression level of each gene was analyzed by qRT-PCR using total mRNA from LNCaP cells, treated with delphinidin and/or TRAIL, and compared with control LNCaP cells. Fold-change was calculated by 2−ΔΔCt relative quantitative analysis. The data are expressed as the mean ± SD for triplicates (*P<0.05 vs. −TRAIL/−DEL).
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Figure 4: TRAIL and delphinidin activate DR5 expression and intrinsic apoptotic pathway(A) Delphinidin induces DR5 in LNCaP and Du145 cells. LNCaP and Du145 cells were treated for 12 h with different concentration of delphinidin (0, 10, 30, 50 μM), and western blot analysis was performed using antibodies against DR5. (B and C) DR5 and BAX expression is critical for the sensitization of TRAIL-mediated apoptosis. LNCaP cells transfected with the scrambled siRNA, DR5 siRNA, or BAX siRNA were further treated with 30 μM delphinidin and 50 ng/ml TRAIL for 12 h. (B) Western blot analysis demonstrated inhibition of caspase-3 cleavage by knockdown of DR5 or BAX and (C) their corresponding antiapoptotic effects. The apoptotic cell death was determined by MTT assay (left) and TUNEL assay (right) kit as described in Materials and Methods. (D) Co-treatment of delphinidin and TRAIL regulates the expression of various apoptosis-related genes at transcriptional level. LNCaP cells were treated with TRAIL (T, 50 ng/ml) and/or delphinidin (D, 30 μM) for 12 h. The expression level of each gene was analyzed by qRT-PCR using total mRNA from LNCaP cells, treated with delphinidin and/or TRAIL, and compared with control LNCaP cells. Fold-change was calculated by 2−ΔΔCt relative quantitative analysis. The data are expressed as the mean ± SD for triplicates (*P<0.05 vs. −TRAIL/−DEL).

Mentions: Because DR5 on the cell surface trigger apoptosis dependent on TRAIL binding, we investigated whether delphinidin induced DR5 protein expression in a dose-dependent manner in LNCaP and Du145 cells. As shown in Fig. 4A, delphinidin treatment up-regulated the expression of DR5 protein in a dose-dependent manner, siRNA-mediated suppression of DR5 effectively blocked delphinidin-stimulated TRAIL-induced caspase-3 activation (Fig. 4B, upper) and apoptosis (Fig. 4C). Next, we investigated whether the modulation of BAX proteins is involved in the sensitization of LNCaP cells to TRAIL-induced apoptosis by delphinidin. Co-treatment of LNCaP cells with delphinidin and TRAIL resulted in the up-regulation of BAX expression, and siRNA-mediated knock-down of BAX markedly inhibited delphinidin-stimulated TRAIL-induced caspase-3 activation (Fig. 4B, bottom). Because the combined treatment with TRAIL and delphinidin leads to the modulation of BCL-2 family proteins related to the intrinsic apoptotic pathway - including the IAPs, MCL-1, and p21 - we evaluated the mRNA expression of these proteins in LNCaP cells. As shown in Fig. 4D, co-treatment resulted in the up-regulation of BAX and p21 as well as DR5 in LNCaP cells; whereas, it significantly reduced the mRNA expression level of XIAP, cIAP-2, Bcl-2, survivin and MCL-1.


Delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis, by inducing DR5 and causing caspase-mediated HDAC3 cleavage.

Ko H, Jeong MH, Jeon H, Sung GJ, So Y, Kim I, Son J, Lee SW, Yoon HG, Choi KC - Oncotarget (2015)

TRAIL and delphinidin activate DR5 expression and intrinsic apoptotic pathway(A) Delphinidin induces DR5 in LNCaP and Du145 cells. LNCaP and Du145 cells were treated for 12 h with different concentration of delphinidin (0, 10, 30, 50 μM), and western blot analysis was performed using antibodies against DR5. (B and C) DR5 and BAX expression is critical for the sensitization of TRAIL-mediated apoptosis. LNCaP cells transfected with the scrambled siRNA, DR5 siRNA, or BAX siRNA were further treated with 30 μM delphinidin and 50 ng/ml TRAIL for 12 h. (B) Western blot analysis demonstrated inhibition of caspase-3 cleavage by knockdown of DR5 or BAX and (C) their corresponding antiapoptotic effects. The apoptotic cell death was determined by MTT assay (left) and TUNEL assay (right) kit as described in Materials and Methods. (D) Co-treatment of delphinidin and TRAIL regulates the expression of various apoptosis-related genes at transcriptional level. LNCaP cells were treated with TRAIL (T, 50 ng/ml) and/or delphinidin (D, 30 μM) for 12 h. The expression level of each gene was analyzed by qRT-PCR using total mRNA from LNCaP cells, treated with delphinidin and/or TRAIL, and compared with control LNCaP cells. Fold-change was calculated by 2−ΔΔCt relative quantitative analysis. The data are expressed as the mean ± SD for triplicates (*P<0.05 vs. −TRAIL/−DEL).
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Related In: Results  -  Collection

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Figure 4: TRAIL and delphinidin activate DR5 expression and intrinsic apoptotic pathway(A) Delphinidin induces DR5 in LNCaP and Du145 cells. LNCaP and Du145 cells were treated for 12 h with different concentration of delphinidin (0, 10, 30, 50 μM), and western blot analysis was performed using antibodies against DR5. (B and C) DR5 and BAX expression is critical for the sensitization of TRAIL-mediated apoptosis. LNCaP cells transfected with the scrambled siRNA, DR5 siRNA, or BAX siRNA were further treated with 30 μM delphinidin and 50 ng/ml TRAIL for 12 h. (B) Western blot analysis demonstrated inhibition of caspase-3 cleavage by knockdown of DR5 or BAX and (C) their corresponding antiapoptotic effects. The apoptotic cell death was determined by MTT assay (left) and TUNEL assay (right) kit as described in Materials and Methods. (D) Co-treatment of delphinidin and TRAIL regulates the expression of various apoptosis-related genes at transcriptional level. LNCaP cells were treated with TRAIL (T, 50 ng/ml) and/or delphinidin (D, 30 μM) for 12 h. The expression level of each gene was analyzed by qRT-PCR using total mRNA from LNCaP cells, treated with delphinidin and/or TRAIL, and compared with control LNCaP cells. Fold-change was calculated by 2−ΔΔCt relative quantitative analysis. The data are expressed as the mean ± SD for triplicates (*P<0.05 vs. −TRAIL/−DEL).
Mentions: Because DR5 on the cell surface trigger apoptosis dependent on TRAIL binding, we investigated whether delphinidin induced DR5 protein expression in a dose-dependent manner in LNCaP and Du145 cells. As shown in Fig. 4A, delphinidin treatment up-regulated the expression of DR5 protein in a dose-dependent manner, siRNA-mediated suppression of DR5 effectively blocked delphinidin-stimulated TRAIL-induced caspase-3 activation (Fig. 4B, upper) and apoptosis (Fig. 4C). Next, we investigated whether the modulation of BAX proteins is involved in the sensitization of LNCaP cells to TRAIL-induced apoptosis by delphinidin. Co-treatment of LNCaP cells with delphinidin and TRAIL resulted in the up-regulation of BAX expression, and siRNA-mediated knock-down of BAX markedly inhibited delphinidin-stimulated TRAIL-induced caspase-3 activation (Fig. 4B, bottom). Because the combined treatment with TRAIL and delphinidin leads to the modulation of BCL-2 family proteins related to the intrinsic apoptotic pathway - including the IAPs, MCL-1, and p21 - we evaluated the mRNA expression of these proteins in LNCaP cells. As shown in Fig. 4D, co-treatment resulted in the up-regulation of BAX and p21 as well as DR5 in LNCaP cells; whereas, it significantly reduced the mRNA expression level of XIAP, cIAP-2, Bcl-2, survivin and MCL-1.

Bottom Line: TRAIL-induced apoptosis in prostate cancer cells pretreated with delphinidin was dependent on death receptor 5 (DR5) and downstream cleavage of histone deacetylase 3 (HDAC3).In conclusion, delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis by inducing DR5, thus causing caspase-mediated HDAC3 cleavage.Our data reveal a potential way of chemoprevention of prostate cancer by enabling TRAIL-mediated apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Oncology, Cheil General Hospital & Women's Healthcare Center, College of Medicine, Dankook University, Seoul, South Korea.

ABSTRACT
TRAIL can induce apoptosis in some cancer cells and is an immune effector in the surveillance and elimination of developing tumors. Yes, some cancers are resistant to TRAIL. Delphinidin, a polyphenolic compound contained in brightly colored fruits and vegetables, has anti-inflammatory, anti-oxidant, and anti-tumorigenic activities. Here we showed that delphinidin sensitized TRAIL-resistant human prostate cancer cells to undergo apoptosis. Cells treated with delphinidin and TRAIL activated the extrinsic and intrinsic pathways of caspase activation. TRAIL-induced apoptosis in prostate cancer cells pretreated with delphinidin was dependent on death receptor 5 (DR5) and downstream cleavage of histone deacetylase 3 (HDAC3). In conclusion, delphinidin sensitizes prostate cancer cells to TRAIL-induced apoptosis by inducing DR5, thus causing caspase-mediated HDAC3 cleavage. Our data reveal a potential way of chemoprevention of prostate cancer by enabling TRAIL-mediated apoptosis.

No MeSH data available.


Related in: MedlinePlus