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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-04-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231716304335 |
| _version_ | 1818475299465068544 |
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| author | Xiaoyu Yang Yi Xu Tao Wang Dan Shu Peixuan Guo Keith Miskimins Steven Y. Qian |
| author_facet | Xiaoyu Yang Yi Xu Tao Wang Dan Shu Peixuan Guo Keith Miskimins Steven Y. Qian |
| author_sort | Xiaoyu Yang |
| collection | DOAJ |
| description | 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. Keywords: COX-catalyzed DGLA peroxidation, Delta-5-desaturase knockdown, ShRNA transfection, Cancer migration and invasion, 5-fluorouracil and gemcitabine, Inhibition of histone deacetylase |
| first_indexed | 2024-12-10T09:11:08Z |
| format | Article |
| id | doaj.art-e3733639fd3947fbbda7b5163cceffd8 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T09:11:08Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-e3733639fd3947fbbda7b5163cceffd82022-12-22T01:55:01ZengElsevierRedox Biology2213-23172017-04-0111653662Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cellsXiaoyu Yang0Yi Xu1Tao Wang2Dan Shu3Peixuan Guo4Keith Miskimins5Steven Y. Qian6Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USADepartment of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USADepartment of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USADivision of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, and College of Medicine, Ohio State University, Columbus, OH 43210, USADivision of Pharmaceutics & Pharmaceutical Chemistry, College of Pharmacy, and College of Medicine, Ohio State University, Columbus, OH 43210, USACancer Biology Research Center, Sanford Research, Sioux Falls, SD 57104, USADepartment of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108, USA; Corresponding author.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. Keywords: COX-catalyzed DGLA peroxidation, Delta-5-desaturase knockdown, ShRNA transfection, Cancer migration and invasion, 5-fluorouracil and gemcitabine, Inhibition of histone deacetylasehttp://www.sciencedirect.com/science/article/pii/S2213231716304335 |
| spellingShingle | Xiaoyu Yang Yi Xu Tao Wang Dan Shu Peixuan Guo Keith Miskimins Steven Y. Qian Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells Redox Biology |
| title | Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells |
| title_full | Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells |
| title_fullStr | Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells |
| title_full_unstemmed | Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells |
| title_short | Inhibition of cancer migration and invasion by knocking down delta-5-desaturase in COX-2 overexpressed cancer cells |
| title_sort | inhibition of cancer migration and invasion by knocking down delta 5 desaturase in cox 2 overexpressed cancer cells |
| url | http://www.sciencedirect.com/science/article/pii/S2213231716304335 |
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