期刊
CELL DEATH & DISEASE
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-019-1723-x
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资金
- Ligue Regionale contre le Cancer comite Grand-Est
- Ligue Nationale contre le Cancer
- Groupe Lipides et Nutrition (GLN)
- French Government [ANR-11-LABX-0021]
Limitation of 5-fluorouracil (5-FU) anticancer efficacy is due to IL-1 beta secretion by myeloid-derived suppressor cells (MDSC), according to a previous pre-clinical report. Release of mature IL-1 beta is a consequence of 5-FU-mediated NLRP3 activation and subsequent caspase-1 activity in MDSC. IL-1 beta sustains tumor growth recovery in 5-FU-treated mice. Docosahexaenoic acid (DHA) belongs to omega-3 fatty acid family and harbors both anticancer and anti-inflammatory properties, which could improve 5-FU chemotherapy. Here, we demonstrate that DHA inhibits 5-FU-induced IL-1 beta secretion and caspase-1 activity in a MDSC cell line (MSC-2). Accordingly, we showed that DHA-enriched diet reduces circulating IL-1 beta concentration and tumor recurrence in 5-FU-treated tumor-bearing mice. Treatment with 5-FU led to JNK activation through ROS production in MDSC. JNK inhibitor SP600125 as well as DHA-mediated JNK inactivation decreased IL-1 beta secretion. The repression of 5-FU-induced caspase-1 activity by DHA supplementation is partially due to beta-arrestin-2-dependent inhibition of NLRP3 inflammasome activity but was independent of JNK pathway. Interestingly, we showed that DHA, through beta-arrestin-2-mediated inhibition of JNK pathway, reduces V5-tagged mature IL-1 beta release induced by 5-FU, in MDSC stably overexpressing a V5-tagged mature IL-1 beta form. Finally, we found a negative correlation between DHA content in plasma and the induction of caspase-1 activity in HLA-DR- CD33(+) CD15(+) MDSC of patients treated with 5-FU-based chemotherapy, strongly suggesting that our data are clinical relevant. Together, these data provide new insights on the regulation of IL-1 beta secretion by DHA and on its potential benefit in 5-FU-based chemotherapy.
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