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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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Induction of apoptosis by γ-T3 treatment. (A) Cell cycle analysis by flow cytometry. Control cells and treated cells incubated with γ-T3 at IC50 for 24-h were subjected to flow cytometry analysis. Note that the sub-G1 population appears after treatment. (B) IC50 time-dependent and 24-h dose-dependent activation (in hrs and μM respectively) of the pro-apoptosis pathway in PC-3. Note that γ-T3 induces activation of the critical molecules (cleaved caspase 3, 7, 8, 9, PARP) and modulate the ratio between the amounts of bcl-2 and bax in a cell dose- and time-dependent fashion. (C) IC50 γ-T3 activates pro-apoptotic genes and suppresses pro-survival genes expression on LNCaP and PC-3 but not on non-tumorigenic prostate epithelial cells (PZ-HPV) for 24-h incubation period.
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fig1: Induction of apoptosis by γ-T3 treatment. (A) Cell cycle analysis by flow cytometry. Control cells and treated cells incubated with γ-T3 at IC50 for 24-h were subjected to flow cytometry analysis. Note that the sub-G1 population appears after treatment. (B) IC50 time-dependent and 24-h dose-dependent activation (in hrs and μM respectively) of the pro-apoptosis pathway in PC-3. Note that γ-T3 induces activation of the critical molecules (cleaved caspase 3, 7, 8, 9, PARP) and modulate the ratio between the amounts of bcl-2 and bax in a cell dose- and time-dependent fashion. (C) IC50 γ-T3 activates pro-apoptotic genes and suppresses pro-survival genes expression on LNCaP and PC-3 but not on non-tumorigenic prostate epithelial cells (PZ-HPV) for 24-h incubation period.

Mentions: To study the mechanism responsible for γ-T3-induced growth inhibition, cell cycle distribution of the cells with or without γ-T3 treatment for 24 h were analysed by flow cytometry. Consequently, treatment of cells with γ-T3 (IC50–95) resulted in an induction of sub-G1 cell population, indicating the presence of apoptotic cells after the treatment (Figure 1A). The proportion of apoptotic cells (sub-G1 fraction) increased in a dose-dependent manner. It is noteworthy that although γ-T3 was previously reported to induce G1 arrest in some cell lines (Mo and Elson, 1999), we did not observe a significant increase of G1 population in prostate cancer cells that were treated with γ-T3. Consistent with the induction of sub-G1 cell population in flow cytometry, activation of procaspase 3, 7, 8, 9 as well as PARP, as evidenced by the appearance of the cleaved products, were observed in PC-3 cells treated with different γ-T3 dosage for 24 h. Downregulation of bcl-2 was also detected after the treatment, although bax expression was not affected, which is likely because of the lack of p53 expression in PC-3 cells (Figure 1B). Meanwhile, these γ-T3-mediated activation of the proapoptotic proteins as well as the change of bcl-2/Bax ratio were in a dose- and time-dependent manner (Figure 1B), consistent with the effect of γ-T3 treatment on inhibition of cell proliferation. In addition, activation of these pro-apoptotic genes after IC50 γ-T3 treatment (Figure 1C) were only observed in PC-3 and LNCaP cells, but not in PZ-HPV-7, indicating that γ-T3 specifically induced apoptosis of androgen-independent prostate cancer cells.


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)

Induction of apoptosis by γ-T3 treatment. (A) Cell cycle analysis by flow cytometry. Control cells and treated cells incubated with γ-T3 at IC50 for 24-h were subjected to flow cytometry analysis. Note that the sub-G1 population appears after treatment. (B) IC50 time-dependent and 24-h dose-dependent activation (in hrs and μM respectively) of the pro-apoptosis pathway in PC-3. Note that γ-T3 induces activation of the critical molecules (cleaved caspase 3, 7, 8, 9, PARP) and modulate the ratio between the amounts of bcl-2 and bax in a cell dose- and time-dependent fashion. (C) IC50 γ-T3 activates pro-apoptotic genes and suppresses pro-survival genes expression on LNCaP and PC-3 but not on non-tumorigenic prostate epithelial cells (PZ-HPV) for 24-h incubation period.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Induction of apoptosis by γ-T3 treatment. (A) Cell cycle analysis by flow cytometry. Control cells and treated cells incubated with γ-T3 at IC50 for 24-h were subjected to flow cytometry analysis. Note that the sub-G1 population appears after treatment. (B) IC50 time-dependent and 24-h dose-dependent activation (in hrs and μM respectively) of the pro-apoptosis pathway in PC-3. Note that γ-T3 induces activation of the critical molecules (cleaved caspase 3, 7, 8, 9, PARP) and modulate the ratio between the amounts of bcl-2 and bax in a cell dose- and time-dependent fashion. (C) IC50 γ-T3 activates pro-apoptotic genes and suppresses pro-survival genes expression on LNCaP and PC-3 but not on non-tumorigenic prostate epithelial cells (PZ-HPV) for 24-h incubation period.
Mentions: To study the mechanism responsible for γ-T3-induced growth inhibition, cell cycle distribution of the cells with or without γ-T3 treatment for 24 h were analysed by flow cytometry. Consequently, treatment of cells with γ-T3 (IC50–95) resulted in an induction of sub-G1 cell population, indicating the presence of apoptotic cells after the treatment (Figure 1A). The proportion of apoptotic cells (sub-G1 fraction) increased in a dose-dependent manner. It is noteworthy that although γ-T3 was previously reported to induce G1 arrest in some cell lines (Mo and Elson, 1999), we did not observe a significant increase of G1 population in prostate cancer cells that were treated with γ-T3. Consistent with the induction of sub-G1 cell population in flow cytometry, activation of procaspase 3, 7, 8, 9 as well as PARP, as evidenced by the appearance of the cleaved products, were observed in PC-3 cells treated with different γ-T3 dosage for 24 h. Downregulation of bcl-2 was also detected after the treatment, although bax expression was not affected, which is likely because of the lack of p53 expression in PC-3 cells (Figure 1B). Meanwhile, these γ-T3-mediated activation of the proapoptotic proteins as well as the change of bcl-2/Bax ratio were in a dose- and time-dependent manner (Figure 1B), consistent with the effect of γ-T3 treatment on inhibition of cell proliferation. In addition, activation of these pro-apoptotic genes after IC50 γ-T3 treatment (Figure 1C) were only observed in PC-3 and LNCaP cells, but not in PZ-HPV-7, indicating that γ-T3 specifically induced apoptosis of androgen-independent prostate cancer cells.

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