Knockdown of delta-5-desaturase promotes the anti-cancer activity of dihomo-γ-linolenic acid and enhances the efficacy of chemotherapy in colon cancer cells expressing COX-2.
Cyclooxygenase (COX), commonly overexpressed in cancer cells, is a major lipid peroxidizing enzyme that metabolizes polyunsaturated fatty acids (ω-3s and ω-6s). The COX-catalyzed free radical peroxidation of arachidonic acid (ω-6) can produce deleterious metabolites (e.g. 2-series prostaglandins) that are implicated in cancer development. Thus, COX inhibition has been intensively investigated as a complementary therapeutic strategy for cancer. However, our previous study has demonstrated that a free radical-derived byproduct (8-hydroxyoctanoic acid) formed from COX-catalyzed peroxidation of dihomo-γ-linolenic acid (DGLA, the precursor of arachidonic acid) can inhibit colon cancer cell growth. We thus hypothesize that the commonly overexpressed COX in cancer (~90% of colon cancer patients) can be taken advantage to suppress cell growth by knocking down delta-5-desaturase (D5D, a key enzyme that converts DGLA to arachidonic acid). In addition, D5D knockdown along with DGLA supplement may enhance the efficacy of chemotherapeutic drugs. After knocking down D5D in HCA-7 colony 29 cells and HT-29 cells (human colon cancer cell lines with high and low COX levels, respectively), the antitumor activity of DGLA was significantly enhanced along with the formation of a threshold range (~0.5-1.0μM) of 8-hydroxyoctanoic acid. In contrast, DGLA treatment did not inhibit cell growth when D5D was not knocked down and only limited amount of 8-hydroxyoctanoic acid was formed. D5D knockdown along with DGLA treatment also enhanced the cytotoxicities of various chemotherapeutic drugs, including 5-fluorouracil, regorafenib, and irinotecan, potentially through the activation of pro-apoptotic proteins, e.g. p53 and caspase 9. For the first time, we have demonstrated that the overexpressed COX in cancer cells can be utilized in suppressing cancer cell growth. This finding may provide a new option besides COX inhibition to optimize cancer therapy. The outcome of this translational research will guide us to develop a novel ω-6-based diet-care strategy in combination with current chemotherapy for colon cancer prevention and treatment.
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA.
Yi
Y
Xu
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA.
Xiaoyu
X
Yang
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, USA.
Pinjing
P
Zhao
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, USA.
Zhongyu
Z
Yang
Department of Computer Science, North Dakota State University, Fargo, ND 58108, USA.
Changhui
C
Yan
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA.
Bin
B
Guo
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA. Electronic address: steven.qian@ndsu.edu.
Steven Y
SY
Qian
D015126:8,11,14-Eicosatrienoic Acid / Q000008:administration & dosage* / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D002210:Caprylates / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics*; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors / Q000235:genetics*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D005609:Free Radicals / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D002210:Caprylates; D000090943:Delta-5 Fatty Acid Desaturase; D043371:Fatty Acids, Omega-6; D005609:Free Radicals; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016718:Arachidonic Acid; C083377:8-hydroxyoctanoic acid; D044943:Fatty Acid Desaturases; D051546:Cyclooxygenase 2; D053453:Caspase 9; D015126:8,11,14-Eicosatrienoic Acid; D005472:Fluorouracil
Cancer chemotherapy; Cell cycle and apoptosis; Colon cancer cell lines (HCA-7 colony 29 and HT-29); Cyclooxygenase and delta-5-desaturase; Dihomo-γ-linolenic acid and ω-6 peroxidation