Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells.
We recently reported that knockdown of delta-5-desaturase (a key enzyme that converts dihomo-γ-linolenic acid, DGLA, to the downstream ω-6 arachidonic acid) promotes formation of an anti-cancer byproduct 8-hydroxyoctanoic acid from cyclooxygenase (COX)-catalyzed DGLA peroxidation. 8-hydroxyoctanoic acid can exert its growth inhibitory effect on cancer cells (e.g. colon and pancreatic cancer) by serving as a histone deacetylase inhibitor. Since histone deacetylase inhibitors have been well-known to suppress cancer cell migration and invasion, we thus tested whether knockdown of delta-5-desaturase and DGLA treatment could also be used to inhibit cancer migration and invasion of colon cancer and pancreatic cancer cells. Wound healing assay, transwell assay and western blot were used to assess cell migration and invasion as well as the associated molecular mechanisms. Formation of threshold level of 8-hydroxyoctanoic acid was quantified from COX-catalyzed DGLA peroxidation in the cancer cells that overexpress COX-2 and their delta-5-desaturases were knocked down by shRNA transfection. Our results showed that knockdown of delta-5-desaturase along with DGLA supplement not only significantly inhibited cell migration, but also improved the efficacies of 5-flurouracil and gemcitabine, two frontline chemotherapy drugs currently used in the treatment of colon and pancreatic cancer, respectively. The molecular mechanism behind these observations is that 8-hydroxyoctanoic acid inhibits histone deacetylase, resulting in downregulation of cancer metastasis promotors, e.g., MMP-2 and MMP-9 as well as upregulation of cancer metastasis suppressor, e.g. E-cadherin. For the first time, we demonstrated that we could take the advantage of the common phenomenon of COX-2 overexpression in cancers to inhibit cancer cell migration and invasion. With the shifting paradigm of COX-2 cancer biology, our research outcome may provide us a novel cancer treatment strategy.
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA.
Xiaoyu
X
Yang
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.
Tao
T
Wang
Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, and College of Medicine, Ohio State University, Columbus, OH 43210, USA.
Dan
D
Shu
Division of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, and College of Medicine, Ohio State University, Columbus, OH 43210, USA.
Peixuan
P
Guo
Cancer Biology Research Center, Sanford Research, Sioux Falls, SD 57104, USA.
Keith
K
Miskimins
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA. Electronic address: steven.qian@ndsu.edu.
Steven Y
SY
Qian
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics*; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
5-fluorouracil and gemcitabine; COX-catalyzed DGLA peroxidation; Cancer migration and invasion; Delta-5-desaturase knockdown; Inhibition of histone deacetylase; ShRNA transfection