Docosahexaenoic acid inhibits both NLRP3 inflammasome assembly and JNK-mediated mature IL-1? secretion in 5-fluorouracil-treated MDSC: implication in cancer treatment.

ABSTRACT: Limitation of 5-fluorouracil (5-FU) anticancer efficacy is due to IL-1? secretion by myeloid-derived suppressor cells (MDSC), according to a previous pre-clinical report. Release of mature IL-1? is a consequence of 5-FU-mediated NLRP3 activation and subsequent caspase-1 activity in MDSC. IL-1? 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? secretion and caspase-1 activity in a MDSC cell line (MSC-2). Accordingly, we showed that DHA-enriched diet reduces circulating IL-1? 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? secretion. The repression of 5-FU-induced caspase-1 activity by DHA supplementation is partially due to ?-arrestin-2-dependent inhibition of NLRP3 inflammasome activity but was independent of JNK pathway. Interestingly, we showed that DHA, through ?-arrestin-2-mediated inhibition of JNK pathway, reduces V5-tagged mature IL-1? release induced by 5-FU, in MDSC stably overexpressing a V5-tagged mature IL-1? 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? secretion by DHA and on its potential benefit in 5-FU-based chemotherapy.

SUBMITTER: Dumont A 

PROVIDER: S-EPMC6584690 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature