Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 96, Issue -, Pages 67-77Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2016.04.016
Keywords
Cancer chemotherapy; Cell cycle and apoptosis; Colon cancer cell lines (HCA-7 colony 29 and HT-29); Cyclooxygenase and delta-5-desaturase; Dihomo-gamma-linolenic acid and omega-6 peroxidation
Funding
- NIH [1R15CA140833, 1R01CA186100-01A1]
- Division Of Computer and Network Systems
- Direct For Computer & Info Scie & Enginr [1305175] Funding Source: National Science Foundation
Ask authors/readers for more resources
Cyclooxygenase (COX), commonly overexpressed in cancer cells, is a major lipid peroxidizing enzyme that metabolizes polyunsaturated fatty acids (omega-3s and omega-6s). The COX-catalyzed free radical peroxidation of arachidonic acid (omega-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-gamma-linolenic acid (DGLA, the precursor of arachidonic acid) can inhibit colon cancer cell growth. We thus hypothesize that the commonly overexpressed COX in cancer (similar to 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 (similar to 0.5-1.0 mu M) 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 omega-6-based diet-care strategy in combination with current chemotherapy for colon cancer prevention and treatment. Published by Elsevier Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available