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Biochim Biophys Acta Mol Cell Res. 2017 Mar;1864(3):498-506. doi: 10.1016/j.bbamcr.2016.12.016. Epub 2016 Dec 18.

Contrasting effects of glutamine deprivation on apoptosis induced by conventionally used anticancer drugs.

Author information

1
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden.
2
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden; College of Veterinary Medicine, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
3
MV Lomonosov Moscow State University, 119991 Moscow, Russia.
4
College of Veterinary Medicine, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
5
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden; MV Lomonosov Moscow State University, 119991 Moscow, Russia.
6
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden; MV Lomonosov Moscow State University, 119991 Moscow, Russia. Electronic address: Vladimir.Gogvadze@ki.se.

Abstract

Tumor cells dependence on glutamine offers a rationale for their elimination via targeting of glutamine metabolism. The aim of this work was to investigate how glutamine deprivation affects the cellular response to conventionally used anticancer drugs. To answer this question, neuroblastoma cells were pre-incubated in a glutamine-free medium and treated with cisplatin or etoposide. Obtained results revealed that glutamine withdrawal affected cellular response to therapeutic drugs in a different manner. Glutamine deprivation suppressed etoposide-induced, but markedly stimulated cisplatin-induced apoptosis. Suppression of etoposide-induced cell death correlated with a downregulation of p53 expression, which, among other functions, regulates the expression of death receptor 5, one of the activators of caspase-8. In contrast, stimulation of cisplatin-induced cell death involved reactive oxygen species-mediated downregulation of FLIP-S, an inhibitor of caspase-8. As a result, the activity of caspase-8 was stimulated causing cleavage of the pro-apoptotic protein Bid, which is involved in the permeabilization of the outer mitochondrial membrane and the release of pro-apoptotic factors, such as cytochrome c from mitochondria. Thus, suppression of glutamine metabolism can sensitize tumor cells to treatment and could be utilized for anti-cancer therapy. However, it should be done cautiously, since adverse effects may occur when combined with an inappropriate therapeutic drug.

KEYWORDS:

Apoptosis; Caspases; Glutamine; Mitochondria; Reactive oxygen species

PMID:
27993669
DOI:
10.1016/j.bbamcr.2016.12.016
[Indexed for MEDLINE]
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