Abstract
Backgroundα-tocopherol (AT) and γ-tocotrienol (GT3) are vitamin E isoforms considered to have potential chemopreventive properties. AT has been widely studied in vitro and in clinical trials with mixed results. The latest clinical study (SELECT trial) tested AT in prostate cancer patients, determined that AT provided no benefit, and could promote cancer. Conversely, GT3 has shown antineoplastic properties in several in vitro studies, with no clinical studies published to date. GT3 causes apoptosis via upregulation of the JNK pathway; however, inhibition results in a partial block of cell death. We compared side by side the mechanistic differences in these cells in response to AT and GT3.MethodsThe effects of GT3 and AT were studied on androgen sensitive LNCaP and androgen independent PC-3 prostate cancer cells. Their cytotoxic effects were analyzed via MTT and confirmed by metabolic assays measuring ATP. Cellular pathways were studied by immunoblot. Quantitative analysis and the determination of relationships between cell signaling events were analyzed for both agents tested. Non-cancerous prostate RWPE-1 cells were also included as a control.ResultsThe RAF/RAS/ERK pathway was significantly activated by GT3 in LNCaP and PC-3 cells but not by AT. This activation is essential for the apoptotic affect by GT3 as demonstrated the complete inhibition of apoptosis by MEK1 inhibitor U0126. Phospho-c-JUN was upregulated by GT3 but not AT. No changes were observed on AKT for either agent, and no release of cytochrome c into the cytoplasm was detected. Caspases 9 and 3 were efficiently activated by GT3 on both cell lines irrespective of androgen sensitivity, but not in cells dosed with AT. Cell viability of non-cancerous RWPE-1 cells was affected neither by GT3 nor AT.Conclusionsc-JUN is a recognized master regulator of apoptosis as shown previously in prostate cancer. However, the mechanism of action of GT3 in these cells also include a significant activation of ERK which is essential for the apoptotic effect of GT3. The activation of both, ERK and c-JUN, is required for apoptosis and may suggest a relevant step in ensuring circumvention of mechanisms of resistance related to the constitutive activation of MEK1.
Highlights
Prostate cancer is the most common malignancy in males, accounting for 19% of new cancer cases in males and 29,430 deaths in 2018 [1]
It has been reported that GT3 may cause apoptosis on prostate cancer cells [9]
Apoptotic effects involving the activation of both, c-JUN and Extracellular-signal-regulated kinase (ERK) have been previously observed in LNCaP and PC3 prostate cancer cells treated with isothiocyanates, compounds present in cruciferous vegetables [15]
Summary
Prostate cancer is the most common malignancy in males, accounting for 19% of new cancer cases in males and 29,430 deaths in 2018 [1]. Γ-tocotrienol (GT3) has been studied in cancers of the breast, pancreas and prostate [9], where it has shown that it inhibits cell proliferation and cell invasion via chemotherapy sensitization, and by suppressing EGFR, NF-κB, and Id proteins, and activating the JNK signaling pathway and caspases 9 and 3. While these studies suggest GT3 as a potential chemopreventive agent that may be useful as an adjunctive treatment option for some forms of prostate cancer, the role of the RAF/RAS/ERK MAPK pathway and the relationship with other signaling cascades has not been clearly established. We present the specific mechanistic differences between AT and GT3 in both androgen-sensitive and androgen-independent prostate cancer cells and its multipronged effect on crucial cell signaling pathways affecting proliferation and survival
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