Docosahexaenoic acid promotes cell cycle arrest and decreases proliferation through WNT/β‐catenin modulation in colorectal cancer cells exposed to γ‐radiation

Abstract

The effects of radiation are known to be potentiated by N‐3 polyunsaturated fatty acids, which modulate several signaling pathways, but the molecular mechanisms through which these fatty acids enhance the anticancer effects of irradiation in colorectal cancer (CRC) treatment remain poorly elucidated. Here, we aimed to ascertain whether the fatty acid docosahexaenoic acid (DHA) exerts a modulating effect on the response elicited by radiation treatment (RT). Two CRC cell lines, Caco‐2 and HT‐29, were exposed to RT, DHA, or both (DHA + RT) for various times, and then cell viability, proliferation, and clonogenicity were assessed. Moreover, cell cycle, apoptosis, and necrosis were analyzed using flow cytometry, and the involvement of WNT/β‐catenin signaling was investigated by immunofluorescence to determine nuclear β‐catenin, GSK3β phosphorylation status, and TCF/LEF‐activity reporter. DHA and RT applied separately diminished the viability of both HT‐29 and Caco‐2 cells, and DHA + RT caused a further reduction in proliferation mainly in HT‐29 cells, particularly in terms of colony formation. Concomitantly, our results verified cell cycle arrest in G0/G1 phase, a reduction of cyclin D1 expression, and a decrease in GSK3β phosphorylation after the combined treatment. Furthermore, immunofluorescence quantification revealed that nuclear β‐catenin was increased in RT‐exposed cells, but this effect was abrogated in cells exposed to DHA + RT, and the results of TCF/LEF‐activity assays confirmed that DHA attenuated the increase in nuclear β‐catenin activity induced by irradiation. Our finding shows that DHA applied in combination with RT enhanced the antitumor effects of irradiation on CRC cells, and that the underlying mechanism involved the WNT/β‐catenin pathway. © 2018 BioFactors, 45(1):24–34, 2019

Dietary Fat and Cancer—Which Is Good, Which Is Bad, and the Body of Evidence

“…Inhibition of proliferation by DHA in MCF-7 cells via pAKT signalling was found in another study [226]. DHA decreased the viability of HT-29 and CaCo-2 colorectal cancer cells and enhanced the effect of irradiation; the underlying mechanism involved the WNT/beta-catenin pathway [227]. Ω-3 PUFAs, particularly DHA, also modulated angiogenesis via miR-126 methylation and VEGF expression in HCT-116 and Caco-2 cells [228].…”

Docosahexaenoic Acid Enhances Oxaliplatin-Induced Autophagic Cell Death via the ER Stress/Sesn2 Pathway in Colorectal Cancer

“…DHA has shown anticancer effects in several types of cancers [15,16,17]. The mechanisms underlying the anticancer effect of DHA reportedly include regulation of Wnt/β-catenin inhibition [18], oxidative DNA damage [19], and mitogen-activated protein kinase activation [14]. Furthermore, our previous studies have revealed that DHA induces autophagy whilst suppressing mTOR in human cervical cancer, prostate cancer, lung cancer, and glioblastoma cells [20,21,22,23].…”

How cancer cells remodel lipid metabolism: strategies targeting transcription factors

“…Docosahexaenoic acid is a major n-3 PUFA involved in anticancer activity. In vitro studies have demonstrated that docosahexaenoic acid inhibits cancer cell proliferation and resistance to irradiation by regulating the Akt and Wnt pathways [ 180 , 181 ]. Docosahexaenoic acid alleviates cancer aggressiveness by modulating the STAT3/nuclear factor kappa B (NF-kB) axis and M2 macrophage polarization [ 182 , 183 ].…”