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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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Jun N-terminal kinase (JNK) activation is involved in γ-T3-induced apoptosis. (A) Cell viability, after incubation with γ-T3 and JNK inhibitor (SP600125) for 24-h, was examined by an MTT assay. Note that the addition of JNK inhibitor alleviates the cytotoxicity of γ-T3 in PC-3, suggesting that JNK mediates the antiproliferation effect of γ-T3. (B) JNK activity after 24-h dose-dependent and IC50 time-dependent γ-T3 treatment (in μM and hours respectively) and was found to be elevated by measuring the phosphorylation levels of MKK4, SAPK/JNK, c-jun and ATF-2. Thus, confirming the involvement of JNK in γ-T3 anticancer property.
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fig3: Jun N-terminal kinase (JNK) activation is involved in γ-T3-induced apoptosis. (A) Cell viability, after incubation with γ-T3 and JNK inhibitor (SP600125) for 24-h, was examined by an MTT assay. Note that the addition of JNK inhibitor alleviates the cytotoxicity of γ-T3 in PC-3, suggesting that JNK mediates the antiproliferation effect of γ-T3. (B) JNK activity after 24-h dose-dependent and IC50 time-dependent γ-T3 treatment (in μM and hours respectively) and was found to be elevated by measuring the phosphorylation levels of MKK4, SAPK/JNK, c-jun and ATF-2. Thus, confirming the involvement of JNK in γ-T3 anticancer property.

Mentions: The c-Jun N-terminal kinase is an evolutionarily conserved serine/threonine protein kinase that is activated by stress and genotoxic agents. JNK phosphorylates the amino terminal of all three Jun transcription factors and ATF-2 members of the AP-1 family. The activated transcription factors modulate gene expression to generate appropriate biological responses, including cell migration and cell death. When PC-3 cells were treated with various doses of γ-T3, a dosage- and time-dependent increase in JNK phosphorylation activities were detected (Figure 3B). Meanwhile, phosphorylation of the JNK downstream effectors such as ATF-2 or c-jun were all upregulated by γ-T3, supporting that JNK-signalling pathway was activated by the γ-T3.


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)

Jun N-terminal kinase (JNK) activation is involved in γ-T3-induced apoptosis. (A) Cell viability, after incubation with γ-T3 and JNK inhibitor (SP600125) for 24-h, was examined by an MTT assay. Note that the addition of JNK inhibitor alleviates the cytotoxicity of γ-T3 in PC-3, suggesting that JNK mediates the antiproliferation effect of γ-T3. (B) JNK activity after 24-h dose-dependent and IC50 time-dependent γ-T3 treatment (in μM and hours respectively) and was found to be elevated by measuring the phosphorylation levels of MKK4, SAPK/JNK, c-jun and ATF-2. Thus, confirming the involvement of JNK in γ-T3 anticancer property.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Jun N-terminal kinase (JNK) activation is involved in γ-T3-induced apoptosis. (A) Cell viability, after incubation with γ-T3 and JNK inhibitor (SP600125) for 24-h, was examined by an MTT assay. Note that the addition of JNK inhibitor alleviates the cytotoxicity of γ-T3 in PC-3, suggesting that JNK mediates the antiproliferation effect of γ-T3. (B) JNK activity after 24-h dose-dependent and IC50 time-dependent γ-T3 treatment (in μM and hours respectively) and was found to be elevated by measuring the phosphorylation levels of MKK4, SAPK/JNK, c-jun and ATF-2. Thus, confirming the involvement of JNK in γ-T3 anticancer property.
Mentions: The c-Jun N-terminal kinase is an evolutionarily conserved serine/threonine protein kinase that is activated by stress and genotoxic agents. JNK phosphorylates the amino terminal of all three Jun transcription factors and ATF-2 members of the AP-1 family. The activated transcription factors modulate gene expression to generate appropriate biological responses, including cell migration and cell death. When PC-3 cells were treated with various doses of γ-T3, a dosage- and time-dependent increase in JNK phosphorylation activities were detected (Figure 3B). Meanwhile, phosphorylation of the JNK downstream effectors such as ATF-2 or c-jun were all upregulated by γ-T3, supporting that JNK-signalling pathway was activated by the γ-T3.

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