Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Apr 12;15(8):1854.
doi: 10.3390/nu15081854.

Molecular Mechanism of Tocotrienol-Mediated Anticancer Properties: A Systematic Review of the Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response

Kok-Lun Pang  1   2 , Chun-Wai Mai  3 , Kok-Yong Chin  1
Affiliations
Review

Molecular Mechanism of Tocotrienol-Mediated Anticancer Properties: A Systematic Review of the Involvement of Endoplasmic Reticulum Stress and Unfolded Protein Response

Kok-Lun Pang et al. Nutrients. .

Abstract

Background: Tocotrienol, a type of vitamin E, is well known for its anti-cancer and other biological activities. This systematic review aims to summarize the involvement of endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) as the underlying molecular mechanisms for the anticancer properties of tocotrienol.

Method: A comprehensive literature search was performed in March 2023 using the PubMed, Scopus, Web of Science, and EMBASE databases. In vitro, in vivo, and human studies were considered.

Result: A total of 840 articles were retrieved during the initial search, and 11 articles that fit the selection criteria were included for qualitative analysis. The current mechanistic findings are based solely on in vitro studies. Tocotrienol induces cancer cell growth arrest, autophagy, and cell death primarily through apoptosis but also through paraptosis-like cell death. Tocotrienol-rich fractions, including α-, γ- and δ-tocotrienols, induce ERS, as evidenced by upregulation of UPR markers and/or ERS-related apoptosis markers. Early endoplasmic reticulum calcium ion release, increased ceramide level, proteasomal inhibition, and upregulation of microRNA-190b were suggested to be essential in modulating tocotrienol-mediated ERS/UPR transduction. Nevertheless, the upstream molecular mechanism of tocotrienol-induced ERS is largely unknown.

Conclusion: ERS and UPR are essential in modulating tocotrienol-mediated anti-cancer effects. Further investigation is needed to elucidate the upstream molecular mechanism of tocotrienol-mediated ERS.

Keywords: ATF6; IRE1; PERK; apoptosis; autophagy; calcium; ceramide; vitamin E.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the Malaysia Toray Science Foundation.

Figures

Figure 1
Figure 1
ERS, downstream UPR pathways, and cell fate. Abbreviations: ℗, phosphorylated; ASK1, apoptosis signal-regulating kinase 1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATF6f, ATF6 fragment or cleaved form; CHOP, CAAT/enhancer-binding protein homologous protein; eIF2α, eukaryotic initiation factor 2 α subunit; ERAD, ER-associated degradation; ERS, endoplasmic reticulum stress; GRP78, 78 kDa glucose-regulated protein; IRE1α, inositol requiring element 1α; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PERK, protein kinase-like endoplasmic reticulum kinase; TRB3, tribbles 3; Xbp1, X-box binding protein 1. The figure was created by authors using BioRender.com on 4 April 2023.
Figure 2
Figure 2
Four isoforms of tocotrienol and their chemical structures.
Figure 3
Figure 3
PRISMA flow chart of the systematic review.
Figure 4
Figure 4
Reported and postulated molecular mechanisms of tocotrienol-mediated ERS and ERS-related cell fate. Abbreviations: ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATF6f, ATF6 fragment or cleaved form; CHOP, CAAT/enhancer-binding protein homologous protein; eIF2α, eukaryotic initiation factor 2 α subunit; ER, endoplasmic reticulum; ERAD, ER-associated degradation; ERO1, ER oxidoreductin 1; IRE1α, inositol requiring element 1α; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PERK, protein kinase-like endoplasmic reticulum kinase; TRB3, tribbles 3; UPR, unfolded protein response; Xbp1, X-box binding protein 1. The figure was created by authors using BioRender.com on 21 March 2023.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sanvictores T., Davis D.D. StatPearls [Internet] StatPearls Publishing; Treasure Island, FL, USA: 2022. Histology, Rough Endoplasmic Reticulum. - PubMed
    1. Mecha M.F., Hutchinson R.B., Lee J.H., Cavagnero S. Protein folding in vitro and in the cell: From a solitary journey to a team effort. Biophys. Chem. 2022;287:106821. doi: 10.1016/j.bpc.2022.106821. - DOI - PMC - PubMed
    1. Almanza A., Carlesso A., Chintha C., Creedican S., Doultsinos D., Leuzzi B., Luís A., McCarthy N., Montibeller L., More S., et al. Endoplasmic reticulum stress signalling—From basic mechanisms to clinical applications. FEBS J. 2019;286:241–278. doi: 10.1111/febs.14608. - DOI - PMC - PubMed
    1. Mei Y., Thompson M.D., Cohen R.A., Tong X. Endoplasmic Reticulum Stress and Related Pathological Processes. J. Pharmacol. Biomed. Anal. 2013;1:1000107. - PMC - PubMed
    1. Sicari D., Delaunay-Moisan A., Combettes L., Chevet E., Igbaria A. A guide to assessing endoplasmic reticulum homeostasis and stress in mammalian systems. FEBS J. 2020;287:27–42. doi: 10.1111/febs.15107. - DOI - PubMed

LinkOut - more resources