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Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways.

Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL - Br. J. Cancer (2008)

Bottom Line: Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population.Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol.Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

View Article: PubMed Central - PubMed

Affiliation: Davos Life Science Pte. Ltd., Cancer Research Laboratory, 11 Biopolis way, #07-03, The Helios 138667, Singapore.

ABSTRACT
Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

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Related in: MedlinePlus

Inactivation of pro-survival pathways by γ-T3. (A) Effect of γ-T3 on the activity of NF-κB pathway was examined by IC50 time-dependent and 24-h dose-dependent western blotting (in hours and μM respectively). Note that nuclear translocation of NF-κB p65 and phosphorylated iκB were inhibited by γ-T3 treatment. (B) Treatment of γ-T3 also resulted in downregulation of Id family proteins and EGF-R in PC-3 cells.
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fig2: Inactivation of pro-survival pathways by γ-T3. (A) Effect of γ-T3 on the activity of NF-κB pathway was examined by IC50 time-dependent and 24-h dose-dependent western blotting (in hours and μM respectively). Note that nuclear translocation of NF-κB p65 and phosphorylated iκB were inhibited by γ-T3 treatment. (B) Treatment of γ-T3 also resulted in downregulation of Id family proteins and EGF-R in PC-3 cells.

Mentions: Although NF-κB was reported to be constitutively activated in PC-3 (Dhanalakshmi et al, 2002), the possibility that γ-T3-induced cell apoptosis attributable to the suppression of NF-κB activation was considered. The NF-κB activities of PC-3 treated with γ-T3 at either different dosages or at IC50 for different periods were measured by examining the translocation of NF-κB subunit p65. As illustrated in Figure 2A, γ-T3 treatment suppressed constitutive NF-κB p65 activity in a dose-dependent and time-dependent manner. The effect of γ-T3 on NF-κB signalling was further explored by examining the expression of other upstream regulators, such as phospho-iκBα/β and iκBα/β. In γ-T3-treated PC-3 cells, a time- and dose-dependent decrease in the level of the phosphorylated IκBα/β were observed (Figure 2A). This is associated with the increase in the level of IκBα/β, as well as an inhibition of NF-κB p65 nuclear translocation. These results indicate that γ-T3 suppressed NF-κB activity through the dephosphorylation and accumulation of IκBα/β.


Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways.

Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL - Br. J. Cancer (2008)

Inactivation of pro-survival pathways by γ-T3. (A) Effect of γ-T3 on the activity of NF-κB pathway was examined by IC50 time-dependent and 24-h dose-dependent western blotting (in hours and μM respectively). Note that nuclear translocation of NF-κB p65 and phosphorylated iκB were inhibited by γ-T3 treatment. (B) Treatment of γ-T3 also resulted in downregulation of Id family proteins and EGF-R in PC-3 cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600692&req=5

fig2: Inactivation of pro-survival pathways by γ-T3. (A) Effect of γ-T3 on the activity of NF-κB pathway was examined by IC50 time-dependent and 24-h dose-dependent western blotting (in hours and μM respectively). Note that nuclear translocation of NF-κB p65 and phosphorylated iκB were inhibited by γ-T3 treatment. (B) Treatment of γ-T3 also resulted in downregulation of Id family proteins and EGF-R in PC-3 cells.
Mentions: Although NF-κB was reported to be constitutively activated in PC-3 (Dhanalakshmi et al, 2002), the possibility that γ-T3-induced cell apoptosis attributable to the suppression of NF-κB activation was considered. The NF-κB activities of PC-3 treated with γ-T3 at either different dosages or at IC50 for different periods were measured by examining the translocation of NF-κB subunit p65. As illustrated in Figure 2A, γ-T3 treatment suppressed constitutive NF-κB p65 activity in a dose-dependent and time-dependent manner. The effect of γ-T3 on NF-κB signalling was further explored by examining the expression of other upstream regulators, such as phospho-iκBα/β and iκBα/β. In γ-T3-treated PC-3 cells, a time- and dose-dependent decrease in the level of the phosphorylated IκBα/β were observed (Figure 2A). This is associated with the increase in the level of IκBα/β, as well as an inhibition of NF-κB p65 nuclear translocation. These results indicate that γ-T3 suppressed NF-κB activity through the dephosphorylation and accumulation of IκBα/β.

Bottom Line: Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population.Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol.Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

View Article: PubMed Central - PubMed

Affiliation: Davos Life Science Pte. Ltd., Cancer Research Laboratory, 11 Biopolis way, #07-03, The Helios 138667, Singapore.

ABSTRACT
Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

Show MeSH
Related in: MedlinePlus