Dihomo-γ-linolenic acid inhibits xenograft tumor growth in mice bearing shRNA-transfected HCA-7 cells targeting delta-5-desaturase.

Abstract

BACKGROUND:

We previously demonstrated that knockdown of delta-5-desaturase via siRNA transfection together with dihomo-γ-linolenic acid supplementation inhibited colon cancer cell growth and migration, by promoting the production of the anti-cancer byproduct 8-hydroxyoctanoic acid from Cyclooxygenase-2-catalyzed dihomo-γ-linolenic acid peroxidation. Here, we extend our study to investigate the effects of delta-5-desaturase-knockdown and the resulting intensified dihomo-γ-linolenic acid peroxidation in xenograft tumor mice model.

METHODS:

Four-week old nude mice bearing the human colon cancer cell HCA-7/C29 vs. its delta-5-desaturase knockdown analog (via shRNA transfection) were subject to 4-week treatments of: vehicle control, dihomo-γ-linolenic acid supplementation, 5-Fluorouracil, and combination of dihomo-γ-linolenic acid and 5-Fluorouracil. Tumor growth was monitored during the treatment. At the endpoint, the mice were euthanized and the tumor tissues were collected for further mechanism analysis.

RESULTS:

Delta-5-desaturase knockdown (shRNA) together with dihomo-γ-linolenic acid supplementation increased 8-hydroxyoctanoic acid production to a threshold level in xenograft tumors, which consequently induced p53-dependent apoptosis and reduced tumors significantly. The promoted 8-hydroxyoctanoic acid formation was also found to suppress the tumors' metastatic potential via regulating MMP-2 and E-cadherin expressions. In addition, our in vivo data showed that delta-5-desaturase knockdown along with dihomo-γ-linolenic acid supplementation resulted in anti-tumor effects comparable to those of 5-Fluorouracil.

CONCLUSIONS:

We have demonstrated that our paradigm-shifting strategy of knocking down delta-5-desaturase and taking advantage of overexpressed Cyclooxygenase-2 in tumor cells can be used for colon cancer suppression. Our research outcome will lead us to develop a better and safer anti-cancer therapy for patients.

• Authors: Yi Xu, Xiaoyu Yang, Di Gao, Liu Yang, Keith Miskimins, Steven Y Qian
• Journal: BMC cancer (BMC Cancer) Vol. 18 Issue 1 Pg. 1268 (Dec 19 2018) ISSN: 1471-2407 [Electronic] England
• PMID: 30567534 (Publication Type: Journal Article)

Chemical References

• Cadherins
• Caprylates
• Delta-5 Fatty Acid Desaturase
• RNA, Small Interfering
• 8-hydroxyoctanoic acid
• Fatty Acid Desaturases
• Cyclooxygenase 2
• Matrix Metalloproteinase 2
• 8,11,14-Eicosatrienoic Acid
• Fluorouracil

Topics

• 8,11,14-Eicosatrienoic Acid (administration & dosage)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Cadherins (genetics)
• Caprylates (metabolism)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Cyclooxygenase 2 (genetics)
• Delta-5 Fatty Acid Desaturase
• Fatty Acid Desaturases (antagonists & inhibitors, genetics)
• Fluorouracil (administration & dosage)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Humans
• Matrix Metalloproteinase 2 (genetics)
• Mice
• Neoplasm Metastasis
• RNA, Small Interfering (genetics)
• Xenograft Model Antitumor Assays