title: Knockdown delta-5-desaturase promotes the formation of a novel free radical byproduct from COX-catalyzed ω-6 peroxidation to induce apoptosis and sensitize pancreatic cancer cells to chemotherapy drugs.
abstract: Recent research has demonstrated that colon cancer cell proliferation can be suppressed in the cells that overexpress COX-2 via generating 8-hydroxyoctanoic acid (a free radical byproduct) during dihomo-γ-linolenic acid (DGLA, an ω-6 fatty acid) peroxidation from knocking down cellular delta-5-desaturase (D5D, the key enzyme for converting DGLA to the downstream ω-6, arachidonic acid). Here, this novel research finding is extended to pancreatic cancer growth, as COX-2 is also commonly overexpressed in pancreatic cancer. The pancreatic cancer cell line, BxPC-3 (with high COX-2 expression and mutated p53), was used to assess not only the inhibitory effects of the enhanced formation of 8-hydroxyoctanoic acid from cellular COX-2-catalyzed DGLA peroxidation but also its potential synergistic and/or additive effect on current chemotherapy drugs. This work demonstrated that, by inducing DNA damage through inhibition of histone deacetylase, a threshold level of 8-hydroxyoctanoic acid achieved in DGLA-treated and D5D-knockdown BxPC-3 cells subsequently induce cancer cell apoptosis. Furthermore, it was shown that a combination of D5D knockdown along with DGLA treatment could also significantly sensitize BxPC-3 cells to various chemotherapy drugs, likely via a p53-independent pathway through downregulating of anti-apoptotic proteins (e.g., Bcl-2) and activating pro-apoptotic proteins (e.g., caspase 3, -9). This study reinforces the supposition that using commonly overexpressed COX-2 for molecular targeting, a strategy conceptually distinct from the prevailing COX-2 inhibition strategy used in cancer treatment, is an important as well as viable alternative to inhibit cancer cell growth. Based on the COX-2 metabolic cascade, the outcomes presented here could guide the development of a novel ω-6-based dietary care strategy in combination with chemotherapy for pancreatic cancer.
authors.affiliation: Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, United States.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Brooks
authors.affiliation: Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, SD 57104, United States.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Miskimins
authors.affiliation: Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, United States. Electronic address: steven.qian@ndsu.edu.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Qian
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D055162:Biocatalysis; D002210:Caprylates / Q000494:pharmacology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D000090943:Delta-5 Fatty Acid Desaturase; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D044943:Fatty Acid Desaturases / Q000235:genetics* / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D015227:Lipid Peroxidation; D010190:Pancreatic Neoplasms; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D002210:Caprylates; D000090943:Delta-5 Fatty Acid Desaturase; D005609:Free Radicals; D003841:Deoxycytidine; C083377:8-hydroxyoctanoic acid; D044943:Fatty Acid Desaturases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015126:8,11,14-Eicosatrienoic Acid; D000093542:Gemcitabine
keywords: 8-Hydroxyoctanoic acid, a free radical byproduct formed from dihomo-γ-linolenic acid metabolism; Cyclooxygenase-(COX-) catalyzed free radical peroxidation; Delta-5-desaturase mediated ω-6 conversion; Pancreatic cancer cell lines; Targeted and chemotherapeutic drugs