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Chem Biol Interact. 2018 Aug 25;292:65-75. doi: 10.1016/j.cbi.2018.06.013. Epub 2018 Jul 2.

Thymoquinone induces apoptosis in bladder cancer cell via endoplasmic reticulum stress-dependent mitochondrial pathway.

Author information

1
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
2
Department of Pharmacology and Toxicology, School of Basic Medical Sciences, Xi'an Medical University, Xi'an, China.
3
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Department of Pharmacology and Toxicology, School of Basic Medical Sciences, Xi'an Medical University, Xi'an, China.
4
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. Electronic address: jinhaif029@126.com.

Abstract

BACKGROUND:

Thymoquinone (TQ), the major active compound isolated from black seed oil (Nigella sativa), has been reported to exhibit anti-inflammatory and anticancer abilities. However, the exact molecular mechanism underlying the anticancer effect of TQ is still poorly understood, especially in regard to TQ's effect on endoplasmic reticulum stress-mediated apoptosis.

METHODS:

The cytotoxicity of TQ on T24 and 253J bladder cancer cells was analyzed by MTT assay, colony formation assay and Annexin V-FITC/PI staining, while SV-HUC-1, the SV-40 immortalized human uroepithelial cell line, was used as a normal control. The change in mitochondrial membrane potential was assessed by JC-1 staining. mRNA expression and protein expression were detected by qPCR and western blotting. Caspase-3 activity was detected by colorimetric assay.

KEY FINDING:

TQ has a significant cytotoxicity on bladder cancer cells and can inhibit their proliferation and induce apoptosis. The protein changes of Bcl-2, Bax, cytochrome c and endoplasmic reticulum stress-related proteins (GRP78, CHOP, and caspase-12) revealed that the anticancer effect of TQ was associated with mitochondrial dysfunction and the endoplasmic reticulum stress pathway. Pretreatment with a pan-caspase inhibitor, Z-VAD-fmk, or an ER stress inhibitor, 4-PBA, or knockdown of CHOP by shRNA can partly reverse the pro-apoptotic effect of TQ by enhancing the expression of the anti-apoptotic protein Bcl-2, blocking the release of cytochrome c and the translocation of Bax from the cytoplasm to mitochondria.

SIGNIFICANCE:

Our findings provide the first demonstration of the anticancer effect of TQ on bladder cancer, and the relationship between ER stress and mitochondrial dysfunction was clearly understood when the apoptosis progressed is revealed.

KEYWORDS:

Apoptosis; Bladder cancer cell; CHOP; Endoplasmic reticulum stress; Mitochondrial dysfunction;; Thymoquinone

PMID:
29981725
DOI:
10.1016/j.cbi.2018.06.013
[Indexed for MEDLINE]
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