Abstract
Emerging evidence suggests that gamma-tocotrienol (γ-T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. γ-T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. Recently, γ-T3 was found to target cancer stem cells (CSCs), leading to suppression of tumour formation and chemosensitisation. Despite its promising anti-cancer potential, the exact mechanisms responsible for the effects of γ-T3 are still largely unknown. Here, we report the identification of Ang-1 (Angiopoietin-1)/Tie-2 as a novel γ-T3 downstream target. In prostate cancer cells, γ-T3 treatment leads to the suppression of Ang-1 at both the mRNA transcript and protein levels. Supplementing the cells with Ang-1 was found to protect them against the anti-CSC effect of γ-T3. Intriguingly, inactivation of Tie-2, a member receptor that mediates the effect of Ang-1, was found to significantly enhance the cytotoxic effect of γ-T3 through activation of AMP-activated protein kinase (AMPK) and subsequent interruption of autophagy. Our results highlighted the therapeutic potential of using γ-T3 in combination with a Tie-2 inhibitor to treat advanced prostate cancer.
Highlights
IntroductionMost of the newly diagnosed cases are at low risk [1], many patients still suffer from disease progression due to the development of metastasis, which is the major contribution to the morbidity and mortality of the disease [2,3]
Prostate cancer is one of the most commonly diagnosed cancers in men worldwide
Consistent with previous studies, we found in our cDNA microarray analysis that γ-T3 significantly suppressed the mRNA level of Ang-1, a common pro-angiogenic factor in prostate cancer cells
Summary
Most of the newly diagnosed cases are at low risk [1], many patients still suffer from disease progression due to the development of metastasis, which is the major contribution to the morbidity and mortality of the disease [2,3]. At this stage, chemotherapy and radiotherapy exhibit only limited benefits. Tocotrienols (T3s) are members of the vitamin E family and have been shown to possess anti-cancer properties [4,5,6,7]. The underlying mechanism responsible for its anti-cancer effect is still far from clear
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