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Mol Carcinog. 2016 Aug;55(8):1213-28. doi: 10.1002/mc.22364. Epub 2015 Jul 24.

The garlic compound ajoene targets protein folding in the endoplasmic reticulum of cancer cells.

Author information

1
Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, South Africa.
2
Department of Biomedical Science, University of Cagliari, Monserrato (CA), Italy.
3
International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa.
4
Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.
5
MRC/UCT Receptor Biology Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
6
Department of Human Biology, Division of Physiology, University of Cape Town, Cape Town, South Africa.

Abstract

Ajoene is a natural allylsulfur compound found in crushed garlic that arrests growth and induces apoptosis in cancer cells. To gain mechanistic insights into the cytotoxicity of ajoene in cancer cells, two fluorescently labelled ajoene analogs with dansyl- (DP) and fluorescein- (FOX) tags were synthesized. The tagged ajoenes were found to retain their activity at inhibiting proliferation and inducing apoptosis in MDA-MB-231 human breast-cancer and WHCO1 human esophageal-cancer cells. Both tagged ajoenes localized to the endoplasmic reticulum (ER) in MDA-MB-231 cells as observed by live cell confocal laser scanning microscopy (CLSM) and confirmed by generating an MDA-MB-231 cell line expressing yellow fluorescent protein (YFP) in the ER. DP appears to S-thiolate multiple protein targets in MDA-MB-231 cells as observed by immunoblotting under non-reducing conditions only; and a competition assay demonstrated that DP and Z-ajoene in fact share the same target. Ajoene S-thiolation interfered with protein folding and led to an accumulation of misfolded protein aggregates and activated the unfolded protein response (UPR). Consistent with this mechanism, increased levels of GRP78 and total ubiquitinated proteins were observed; and an ER-folded protein, type-1 collagen, was tracked to the proteasome following ajoene treatment. The intracellular protein aggregates were observed by CLSM and transmission electron microscopy (TEM). This is the first time that ajoene has been shown to target protein folding in the ER of cancer cells.

KEYWORDS:

ajoene; cancer prevention; endoplasmic reticulum; garlic; protein folding

PMID:
26207910
DOI:
10.1002/mc.22364
[Indexed for MEDLINE]

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