RESUMEN
Metastatic breast cancer cannot be cured, and alteration of fatty acid metabolism contributes to tumor progression and metastasis. Here, we were interested in the elongation of very long-chain fatty acids protein 5 (Elovl5) in breast cancer. We observed that breast cancer tumors had a lower expression of Elovl5 than normal breast tissues. Furthermore, low expression of Elovl5 is associated with a worse prognosis in ER+ breast cancer patients. In accordance with this finding, decrease of Elovl5 expression was more pronounced in ER+ breast tumors from patients with metastases in lymph nodes. Although downregulation of Elovl5 expression limited breast cancer cell proliferation and cancer progression, suppression of Elovl5 promoted EMT, cell invasion and lung metastases in murine breast cancer models. The loss of Elovl5 expression induced upregulation of TGF-ß receptors mediated by a lipid-droplet accumulation-dependent Smad2 acetylation. As expected, inhibition of TGF-ß receptors restored proliferation and dampened invasion in low Elovl5 expressing cancer cells. Interestingly, the abolition of lipid-droplet formation by inhibition of diacylglycerol acyltransferase activity reversed induction of TGF-ß receptors, cell invasion, and lung metastasis triggered by Elovl5 knockdown. Altogether, we showed that Elovl5 is involved in metastasis through lipid droplets-regulated TGF-ß receptor expression and is a predictive biomarker of metastatic ER+ breast cancer.
Asunto(s)
Neoplasias de la Mama , Elongasas de Ácidos Grasos/metabolismo , Neoplasias Pulmonares , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal , Femenino , Humanos , Lípidos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Metástasis de la Neoplasia , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Limitation of 5-fluorouracil (5-FU) anticancer efficacy is due to IL-1ß secretion by myeloid-derived suppressor cells (MDSC), according to a previous pre-clinical report. Release of mature IL-1ß is a consequence of 5-FU-mediated NLRP3 activation and subsequent caspase-1 activity in MDSC. IL-1ß 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-1ß secretion and caspase-1 activity in a MDSC cell line (MSC-2). Accordingly, we showed that DHA-enriched diet reduces circulating IL-1ß 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-1ß secretion. The repression of 5-FU-induced caspase-1 activity by DHA supplementation is partially due to ß-arrestin-2-dependent inhibition of NLRP3 inflammasome activity but was independent of JNK pathway. Interestingly, we showed that DHA, through ß-arrestin-2-mediated inhibition of JNK pathway, reduces V5-tagged mature IL-1ß release induced by 5-FU, in MDSC stably overexpressing a V5-tagged mature IL-1ß 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-1ß secretion by DHA and on its potential benefit in 5-FU-based chemotherapy.
