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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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Inhibition of cell invasion by γ-T3 treatment. (A) 24-h dose-dependent and IC50 time-dependent γ-T3 treatment induces the expression of epithelial markers (E-cadherin, γ-catenin), but suppresses the expression of mesenchymal markers (vimentin, twist and α-SMA) and E-cadherin's repressor (snail). (B) The invasive androgen-independent PCa cells (PC-3) treated with the indicated dosage of γ-T3 was harvested and then plated into the Matrigel-coated (0.5 mg ml−1) insert. Cells invaded through the membrane were stained with crystal violet and the images were photographed under a microscope. After being lysed with extraction buffer, intensity at 595 nm was measured.
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fig4: Inhibition of cell invasion by γ-T3 treatment. (A) 24-h dose-dependent and IC50 time-dependent γ-T3 treatment induces the expression of epithelial markers (E-cadherin, γ-catenin), but suppresses the expression of mesenchymal markers (vimentin, twist and α-SMA) and E-cadherin's repressor (snail). (B) The invasive androgen-independent PCa cells (PC-3) treated with the indicated dosage of γ-T3 was harvested and then plated into the Matrigel-coated (0.5 mg ml−1) insert. Cells invaded through the membrane were stained with crystal violet and the images were photographed under a microscope. After being lysed with extraction buffer, intensity at 595 nm was measured.

Mentions: Although γ-T3 has been shown to have antiproliferation effect on many cancers, it is not clear if it affects cancer metastasis. Therefore, we examined whether γ-T3 could suppress the invasive ability of the prostate cancer cells. As shown in Figure 4B, using matrigel-invasion assay, we found that γ-T3-treated (IC50) PC-3 cells for 24 h showed an at least 2.5-time lower invasion capability compared with the untreated control as evidenced by a decrease in the number of cells invaded through the matrigel layer. This inhibitory effect on cell invasion was not the result of cell growth inhibition induced by γ-T3 as the number of viable cells added into the invasion chamber were the same. These results indicate that γ-T3 is able to inhibit the invasion ability of PCa cells, independent to their cytotoxic effects.


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)

Inhibition of cell invasion by γ-T3 treatment. (A) 24-h dose-dependent and IC50 time-dependent γ-T3 treatment induces the expression of epithelial markers (E-cadherin, γ-catenin), but suppresses the expression of mesenchymal markers (vimentin, twist and α-SMA) and E-cadherin's repressor (snail). (B) The invasive androgen-independent PCa cells (PC-3) treated with the indicated dosage of γ-T3 was harvested and then plated into the Matrigel-coated (0.5 mg ml−1) insert. Cells invaded through the membrane were stained with crystal violet and the images were photographed under a microscope. After being lysed with extraction buffer, intensity at 595 nm was measured.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Inhibition of cell invasion by γ-T3 treatment. (A) 24-h dose-dependent and IC50 time-dependent γ-T3 treatment induces the expression of epithelial markers (E-cadherin, γ-catenin), but suppresses the expression of mesenchymal markers (vimentin, twist and α-SMA) and E-cadherin's repressor (snail). (B) The invasive androgen-independent PCa cells (PC-3) treated with the indicated dosage of γ-T3 was harvested and then plated into the Matrigel-coated (0.5 mg ml−1) insert. Cells invaded through the membrane were stained with crystal violet and the images were photographed under a microscope. After being lysed with extraction buffer, intensity at 595 nm was measured.
Mentions: Although γ-T3 has been shown to have antiproliferation effect on many cancers, it is not clear if it affects cancer metastasis. Therefore, we examined whether γ-T3 could suppress the invasive ability of the prostate cancer cells. As shown in Figure 4B, using matrigel-invasion assay, we found that γ-T3-treated (IC50) PC-3 cells for 24 h showed an at least 2.5-time lower invasion capability compared with the untreated control as evidenced by a decrease in the number of cells invaded through the matrigel layer. This inhibitory effect on cell invasion was not the result of cell growth inhibition induced by γ-T3 as the number of viable cells added into the invasion chamber were the same. These results indicate that γ-T3 is able to inhibit the invasion ability of PCa cells, independent to their cytotoxic effects.

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