Dihomo-γ-linolenic acid inhibits xenograft tumor growth in mice bearing shRNA-transfected HCA-7 cells targeting delta-5-desaturase

Abstract

BackgroundWe previously demonstrated that knockdown of delta-5-desaturase via siRNA transfection together with dihomo-γ-linolenic acid supplementation inhibited colon cancer cell growth and migration, by promoting the production of the anti-cancer byproduct 8-hydroxyoctanoic acid from Cyclooxygenase-2-catalyzed dihomo-γ-linolenic acid peroxidation. Here, we extend our study to investigate the effects of delta-5-desaturase-knockdown and the resulting intensified dihomo-γ-linolenic acid peroxidation in xenograft tumor mice model.MethodsFour-week old nude mice bearing the human colon cancer cell HCA-7/C29 vs. its delta-5-desaturase knockdown analog (via shRNA transfection) were subject to 4-week treatments of: vehicle control, dihomo-γ-linolenic acid supplementation, 5-Fluorouracil, and combination of dihomo-γ-linolenic acid and 5-Fluorouracil. Tumor growth was monitored during the treatment. At the endpoint, the mice were euthanized and the tumor tissues were collected for further mechanism analysis.ResultsDelta-5-desaturase knockdown (shRNA) together with dihomo-γ-linolenic acid supplementation increased 8-hydroxyoctanoic acid production to a threshold level in xenograft tumors, which consequently induced p53-dependent apoptosis and reduced tumors significantly. The promoted 8-hydroxyoctanoic acid formation was also found to suppress the tumors’ metastatic potential via regulating MMP-2 and E-cadherin expressions. In addition, our in vivo data showed that delta-5-desaturase knockdown along with dihomo-γ-linolenic acid supplementation resulted in anti-tumor effects comparable to those of 5-Fluorouracil.ConclusionsWe have demonstrated that our paradigm-shifting strategy of knocking down delta-5-desaturase and taking advantage of overexpressed Cyclooxygenase-2 in tumor cells can be used for colon cancer suppression. Our research outcome will lead us to develop a better and safer anti-cancer therapy for patients.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5185-9) contains supplementary material, which is available to authorized users.

Specific delivery of delta-5-desaturase siRNA via RNA nanoparticles supplemented with dihomo-γ-linolenic acid for colon cancer suppression

“…Recent studies from the Qian group revealed that the COX-2-catalyzed peroxidation of dihomo-γ-linolenic acid (DGLA, an upstream ω-6 fatty acid) can produce a distinct anti-cancer byproduct, 8-hydroxyloctanoic acid (8-HOA), which may act as a histone deacetylase inhibitor (HDACi) in an autocrine manner to suppress cancer cell/tumor growth and migration [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. However, DGLA can be effectively converted to its downstream ω-6 fatty acid arachidonic acid by delta-5-desaturase (D5D), which greatly restricts DGLA's bioavailability.…”

“…However, DGLA can be effectively converted to its downstream ω-6 fatty acid arachidonic acid by delta-5-desaturase (D5D), which greatly restricts DGLA's bioavailability. Thus, a D5D knockdown strategy ( via siRNA transfection) was proposed and demonstrated to successfully limit the conversion from DGLA to arachidonic acid and promote 8-HOA formation, thereby inhibiting cancer cell growth and migration [29], [30], [31], [32], [33], [34]. The promoted 8-HOA was found to induce p53-dependent apoptosis and cause DNA damage as a result of inhibiting histone deacetylase (HDAC) in various types of cancer [29], [30], [31], [32], [33], [34].…”

A prospective study of erythrocyte polyunsaturated fatty acids and risk of colorectal serrated polyps and conventional adenomas

“…DGLA is a substrate of prostaglandin‐endoperoxide synthase 2, giving rise to prostaglandin E1 (PGE 1 ), an inflammation‐suppressing eicosanoids 44,45 . Thus, the anti‐inflammatory property of DGLA and its ability to compete with AA in the synthesis of pro‐inflammatory products may reduce risk of colorectal cancer 45,46 . As for EDA, a previous study found that EDA was inversely associated with colorectal cancer.…”

EpCAM-Targeted 3WJ RNA Nanoparticle Harboring Delta-5-Desaturase siRNA Inhibited Lung Tumor Formation via DGLA Peroxidation

“…injection, 0.5 mL U-100 Insulin Syringe, 29G × 1/2, twice a week, 20 μM in 50 μL PBS), and DGLA+ 3WJ-EpCAM-D5D siRNA nanoparticle group. 49 All of the treatments were for 4 weeks. At the end of the treatment, nude mice were euthanized with an overdose of pentobarbital (200 mg/kg, intraperitoneally [i.p.]).…”

“…The tumors were also visualized by the Vevo 3100 VisualSonics Imaging System (FUJIFILM VisualSonics, Toronto, ON, Canada) weekly. 49 …”