Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA.
Department of Transplantation, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
Redox Biol. 2019 Jan;20:236-246. doi: 10.1016/j.redox.2018.10.001. Epub 2018 Oct 15.
We recently reported that siRNA-knockdown of delta-5-desaturase (D5D), the rate-limiting enzyme converting upstream ω - 6 dihomo-γ-linolenic acid (DGLA) to arachidonic acid, promoted formation of the anti-cancer byproduct 8-hydroxyoctanoic acid (8-HOA) from COX-2-catalyzed DGLA peroxidation, consequently suppressing pancreatic cancer cell growth, migration and invasion. In this study, we have further investigated the anti-tumor effects of D5D-knockdown and the resulting intensified COX-2-catalyzed DGLA peroxidation in subcutaneous xenograft tumors. Four-week old female nude mice (Jackson Laboratory, J:Nu-007850) were injected with human pancreatic cancer cell line BxPC-3 or its D5D knockdown counterpart (via shRNA), followed by 4-week treatments of: vehicle control, DGLA supplementation (8 mg/mouse, twice a week), gemcitabine (30 mg/kg, twice a week), and a combination of DGLA and gemcitabine. In D5D-knockdown tumors, DGLA supplementation promoted 8-HOA formation to a threshold level (> 0.3 µg/g) and resulted in significant tumor reduction (30% vs. control). The promoted 8-HOA not only induced apoptosis associated with altered expression of Bcl-2, cleaved PARP, procaspase 3 and procaspase 9, but also suppressed the tumor metastatic potential via altering MMP-2 and E-cadherin expression. DGLA supplementation resulted in similar anti-tumor effects to those of gemcitabine in our experiments, while the combined treatment led to most significant inhibitory effect on D5D-knockdown tumor growth (70% reduction vs. control). Compared to conventional COX-2 inhibition in cancer treatment, our new strategy that takes advantage of overexpressed COX-2 in cancer cells and tumors, and of abundant ω - 6 fatty acids in the daily diet, should lead us to develop a better and safer anti-pancreatic cancer therapy for patients.
我们最近报道称，δ-5-去饱和酶（D5D）的 siRNA 敲低，即催化上游 ω-6 二同型-γ-亚麻酸（DGLA）转化为花生四烯酸的限速酶，促进了 COX-2 催化的 DGLA 过氧化作用产生抗癌副产物 8-羟基壬酸（8-HOA），从而抑制胰腺癌细胞的生长、迁移和侵袭。在这项研究中，我们进一步研究了 D5D 敲低和由此增强的 COX-2 催化的 DGLA 过氧化作用对皮下异种移植肿瘤的抗肿瘤作用。将 4 周龄雌性裸鼠（Jackson Laboratory，J：Nu-007850）注射人胰腺癌细胞系 BxPC-3 或其 D5D 敲低对应物（通过 shRNA），然后进行 4 周的治疗：载体对照、DGLA 补充（8mg/只，每周两次）、吉西他滨（30mg/kg，每周两次）和 DGLA 与吉西他滨的联合治疗。在 D5D 敲低的肿瘤中，DGLA 补充促进了 8-HOA 的形成达到阈值水平（>0.3μg/g），并导致肿瘤显著减少（与对照相比减少 30%）。促进的 8-HOA 不仅诱导与 Bcl-2、裂解 PARP、procaspase 3 和 procaspase 9 的表达改变相关的细胞凋亡，还通过改变 MMP-2 和 E-钙黏蛋白的表达来抑制肿瘤转移潜力。在我们的实验中，DGLA 补充与吉西他滨具有相似的抗肿瘤作用，而联合治疗对 D5D 敲低肿瘤生长的抑制作用最为显著（与对照相比减少 70%）。与癌症治疗中的传统 COX-2 抑制相比，我们的新策略利用了癌细胞和肿瘤中过表达的 COX-2，以及日常饮食中丰富的 ω-6 脂肪酸，应该使我们能够为患者开发出更好、更安全的抗胰腺癌治疗方法。
