Metabolic Shift Induced by ω -3 PUFAs and Rapamycin Lead to Cancer Cell Death

• Published in: Cellular physiology and biochemistry Vol. 48; no. 6; pp. 2318 - 2336
• Main Authors: Zhu, Shenglong, Feng, Ninghan, Lin, Guangxiao, Tong, Yuelin, Jiang, Xuan, Yang, Qin, Wang, Shunhe, Chen, Wei, He, Zhao, Chen, Yong Q
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2018; Cell Physiol Biochem Press GmbH & Co KG
• Subjects: Adenosine Triphosphate - metabolism; Animals; Apoptosis; Apoptosis - drug effects; Autophagy; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer metabolism; Cancer therapies; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell death; Cell growth; Cell Line, Tumor; Consent; Disease Models, Animal; Drug resistance; Ethics; Fatty acids; Fatty Acids, Omega-3 - pharmacology; Fatty Acids, Omega-3 - therapeutic use; Female; Gastric cancer; Humans; Kinases; Lactic Acid - metabolism; Malondialdehyde - metabolism; MCF-7 Cells; Metabolic disorders; Metabolomics; Mice; Microtubule-Associated Proteins - metabolism; Original Paper; Oxidative Phosphorylation - drug effects; Rapamycin; Reactive Oxygen Species - metabolism; Sirolimus - pharmacology; Sirolimus - therapeutic use; ω-3 PUFAs; China; Rapamycin; Breast cancer; Cancer metabolism; ω-3 PUFAs
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000492648

Background/Aims: Rapamycin (Rp), the main mammalian target of rapamycin complex inhibitor, is a promising therapeutic agent for breast cancer. However, metabolic disorders and drug resistance reduce its efficacy. Epidemiological, clinical, and experimental studies have demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) significantly reduce the incidence and mortality of breast cancer and improve metabolic disorders. Methods: Three breast cancer cell lines and immunocompetent and immunodeficient mice were used to evaluate the therapeutic effects of Rp plus ω-3 PUFA treatment. The production of reactive oxygen species (ROS) and glucose uptake were examined by flow cytometry. Metabolic shift was examined by metabonomics, seahorse experiments, and western blot analysis. Results: We found that ω-3 PUFAs and Rp synergistically induced cell cycle arrest and apoptosis in vitro and in vivo, accompanied by autophagy blockage. In addition, Rp-induced hypertriglyceridemia and hypercholesterolemia were completely abolished by ω-3 PUFA supplementation. Moreover, the combined treatment of ω-3 PUFA and Rp significantly inhibited glycolysis and glutamine metabolism. The anti-tumor effects of this combination treatment were dependent on ROS production, which was increased by β-oxidation and oxidative phosphorylation. Conclusion: Our study revealed that ω-3 PUFA enhanced the anti-tumor activity of Rp while minimizing its side effects in vitro and in vivo. These results provide novel insights into the mechanisms underlying the potential beneficial effects of Rp combined with ω-3 PUFAs on the prevention of breast cancer.