Gamma-Tocotrienol Induces Apoptosis in Prostate Cancer Cells by Targeting the Ang-1/Tie-2 Signalling Pathway

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....

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Published inInternational journal of molecular sciences Vol. 20; no. 5; p. 1164
Main Authors Tang, Kai Dun, Liu, Ji, Russell, Pamela J, Clements, Judith A, Ling, Ming-Tat
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 07.03.2019
MDPI
Subjects
Angiogenesis
angiopoietin-1
Apoptosis
Autocrine signalling
Autophagy
Cell growth
Chemotherapy
Cytotoxicity
Epidermal growth factor
Epidermal growth factor receptors
Epithelial cells
Experiments
gamma-tocotrienol and autophagy
Growth factors
Hypotheses
Kinases
mRNA
NF-κB protein
Phosphorylation
Prostate cancer
Protein expression
Proteins
Radiation therapy
Secretion
Signal transduction
Tie-2
Tumor cell lines
angiopoietin-1
prostate cancer
gamma-tocotrienol and autophagy
Tie-2
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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.
AbstractList 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.
At this stage, chemotherapy and radiotherapy exhibit only limited benefits. [...]advanced prostate cancer remains incurable with current treatment strategies. [8], a tocotrienol-rich fraction (TRF) was able to inhibit the growth and induce apoptosis of human prostate cancer cell lines (LNCaP, DU145, PC-3), but not in normal human prostate epithelial cells, suggesting that it specifically targets cancer cells. NF-κB plays an important role in regulating cell survival through the induction of a series of anti-apoptotic proteins in cancer cells. [...]γ-T3-induced apoptosis was also found to be associated with the suppression of NF-κB, epidermal growth factor receptor (EGFR), and Id family proteins (Id1 and Id3) in prostate cancer [10]. To validate this finding, we first treated PC-3 cells with 10 µg/mL γ-T3 for 3 days under a serum-free condition [9]. γ-T3 not only significantly suppressed the mRNA level of Ang-1 in PC-3 cells, but also inhibited Ang-1 secretion from the cells (Figure 1A,B). Since Ang-1 has been shown to regulate prostate CSCs by functioning as an autocrine factor [18], we speculate that the anti-CSC function of T3 reported in our previous study may be due to the suppression of Ang-1 secretion.
Author Liu, Ji
Russell, Pamela J
Ling, Ming-Tat
Clements, Judith A
Tang, Kai Dun
AuthorAffiliation The School of Biomedical Sciences, Australian Prostate Cancer Research Centre-Queensland & Institute of Health and Biomedical Innovation, Queensland University of Technology and The Translational Research Institute, Queensland 4102, Australia; Ji.Liu@qimrberghofer.edu.au (J.L.); pamela.russell@qut.edu.au (P.J.R.); j.clements@qut.edu.au (J.A.C.)
AuthorAffiliation_xml – name: The School of Biomedical Sciences, Australian Prostate Cancer Research Centre-Queensland & Institute of Health and Biomedical Innovation, Queensland University of Technology and The Translational Research Institute, Queensland 4102, Australia; Ji.Liu@qimrberghofer.edu.au (J.L.); pamela.russell@qut.edu.au (P.J.R.); j.clements@qut.edu.au (J.A.C.)
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  givenname: Ming-Tat
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  organization: The School of Biomedical Sciences, Australian Prostate Cancer Research Centre-Queensland & Institute of Health and Biomedical Innovation, Queensland University of Technology and The Translational Research Institute, Queensland 4102, Australia. mingtat.ling@qut.edu.au
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30866453$$D View this record in MEDLINE/PubMed
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Keywords angiopoietin-1
prostate cancer
gamma-tocotrienol and autophagy
Tie-2
Language English
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Snippet 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...
At this stage, chemotherapy and radiotherapy exhibit only limited benefits. [...]advanced prostate cancer remains incurable with current treatment strategies....
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StartPage 1164
SubjectTerms Angiogenesis
angiopoietin-1
Apoptosis
Autocrine signalling
Autophagy
Cell growth
Chemotherapy
Cytotoxicity
Epidermal growth factor
Epidermal growth factor receptors
Epithelial cells
Experiments
gamma-tocotrienol and autophagy
Growth factors
Hypotheses
Kinases
mRNA
NF-κB protein
Phosphorylation
Prostate cancer
Protein expression
Proteins
Radiation therapy
Secretion
Signal transduction
Tie-2
Tumor cell lines
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Title Gamma-Tocotrienol Induces Apoptosis in Prostate Cancer Cells by Targeting the Ang-1/Tie-2 Signalling Pathway
URI https://www.ncbi.nlm.nih.gov/pubmed/30866453
https://www.proquest.com/docview/2332230867
https://search.proquest.com/docview/2191354459
https://pubmed.ncbi.nlm.nih.gov/PMC6429150
https://doaj.org/article/c2d4144844cc4f4f8f6c03bab2901579
Volume 20
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