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Free Radic Biol Med. 2016 Aug;97:342-350. doi: 10.1016/j.freeradbiomed.2016.06.028. Epub 2016 Jun 28.

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.

Author information

1
Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, United States.
2
Cancer Biology Research Center, Sanford Research, Sioux Falls, SD 57104, United States.
3
Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, United States. Electronic address: steven.qian@ndsu.edu.

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.

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

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