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Abstract
Limitation of 5-fluorouracil (5-FU) anticancer efficacy is due to IL-1β secretion by myeloid-derived suppressor cells (MDSC), according to a previous pre-clinical report. Release of mature IL-1β is a consequence of 5-FU-mediated NLRP3 activation and subsequent caspase-1 activity in MDSC. IL-1β 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-1β secretion and caspase-1 activity in a MDSC cell line (MSC-2). Accordingly, we showed that DHA-enriched diet reduces circulating IL-1β 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-1β secretion. The repression of 5-FU-induced caspase-1 activity by DHA supplementation is partially due to β-arrestin-2-dependent inhibition of NLRP3 inflammasome activity but was independent of JNK pathway. Interestingly, we showed that DHA, through β-arrestin-2-mediated inhibition of JNK pathway, reduces V5-tagged mature IL-1β release induced by 5-FU, in MDSC stably overexpressing a V5-tagged mature IL-1β 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-1β secretion by DHA and on its potential benefit in 5-FU-based chemotherapy.
Highlights
In solid cancers, including colorectal (CRC), pancreatic, gastric, breast, and ovarian cancers, the antimetabolite5-Fluorouracil (5-FU) represents one of the most commonly used chemotherapeutic drug[1]
We showed that injections of nonesterified Docosahexaenoic acid (DHA) before and after the single intraperitoneal injection of 5-FU in EL4-bearing mice, promoted a more drastic tumor regression and delayed tumor growth recovery compared to 5-FU-treated mice with intraperitoneal injections of vehicle (Fig. S1g)
We investigated the correlation between the percentage of DHA in total plasma FAs prior to a 5-FU-based chemotherapy (D0) and a change of caspase-1 activity in circulating myeloid-derived suppressor cells (MDSC) purified on D0 compared to those purified one day after chemotherapy (D1), in patients with colorectal cancer (n = 46)
Summary
In solid cancers, including colorectal (CRC), pancreatic, gastric, breast, and ovarian cancers, the antimetabolite. The dual role of 5-FU on MDSC comes from its ability on the one hand to eradicate the protumoral myeloid cells and alleviate anticancer immune suppression[6] and on the other hand to trigger IL-1β secretion sustaining tumor growth[7]. DHA alone or in association with chemotherapeutic agents promotes cancer cell apoptosis and modify cancer neoangiogenesis resulting in an inhibitory effect on tumor growth[12,13,16,19]. We carried out pre-clinical studies to investigate the ability of DHA to improve 5-FU antineoplastic action, by limiting IL-1β release by MDSC. Thanks to blood samples from patients submitted to 5-FU-based chemotherapy, we evaluated the correlation between plasma DHA levels and caspase-1 activation in MDSC
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