Omega 3-DHA and Delta-Tocotrienol Modulate Lipid Droplet Biogenesis and Lipophagy in Breast Cancer Cells: the Impact in Cancer Aggressiveness

Abstract

Omega 3-docosahexaenoic acid (DHA) and vitamin E Delta-tocotrienol (Delta-T3) are extensively studied as protective nutrients against cancer development. Little is known about the biological mechanisms targeted by these bioactive molecules on lipid droplet (LD) biogenesis, an important breast cancer aggressiveness marker, and the occurrence of lipophagy in breast cancer cells. The aim of this study was to investigate the effect of DHA, Delta-T3 and DHA plus Delta-T3 co-treatment in LD biogenesis and lipophagy process in triple negative breast cancer cell line MDA-MB-231. Cells were treated with 50 μM DHA and/or 5 μM Delta-T3. Our results demonstrated that DHA can trigger an increase in LD biogenesis and co-treatment with Delta-T3 was able to reduce this LD biogenesis. In addition, we showed that a higher cytoplasmic LD content is associated with a higher breast cancer cells malignance and proliferation. Reduction of cytoplasmic LD content by silencing ADRP (adipose differentiation-related protein), a structural LD protein, also decreased cell proliferation in MDA-MB-231 cells. Treatment with DHA and Delta-T3 alone or co-treatment did not reduce cell viability. Moreover, we showed here that DHA can trigger lipophagy in MDA-MB-231 cells and DHA plus Delta-T3 co-treatment was able to enhance this lipophagy process. Our findings demonstrated that co-treatment with DHA plus Delta-T3 in MDA-MB-231 cells could reduce LD biogenesis and potentiate lipophagy in these cells, possibly having a positive impact to inhibit breast cancer malignancy. Therefore, suitable doses of DHA and Delta-T3 vitamin E isoform supplementation can be a prominent tool in therapeutic treatments against breast cancer.

The Effect of Diet Supplementation with Pomegranate and Bitter Melon on Lipidomic Profile of Serum and Cancerous Tissues of Rats with Mammary Tumours

“…Additionally, Straka et al [55] and Maillard et al [56] observed increased accumulation of C20:5, c,c,c,c,c-∆5,8,11,14,17 and C22:6, c,c,c,c,c,c-∆4,7,10,13,16,19 in breast adipose tissue of women at high risk of breast cancer; the accumulation resulted from both diet supplementation and increased fish consumption. These results are in line with numerous studies demonstrating anticarcinogenic properties of long chain PUFA [36,57,58]. Novel preventive and therapeutic approaches include the attempts to use nanoparticle formulations for PUFA internalisation into cancer cells [59].…”

Dietary Fat and Cancer—Which Is Good, Which Is Bad, and the Body of Evidence

“…There are other targets in lipid signalling pathways [329], and potential intervention may include modulation of lipid droplets biogenesis and lipophagy [330], but the research on the mechanisms involved in these pathways and their role in the genesis and progression of cancer is still ongoing. Thus, the development of substances that would effectively disrupt lipid metabolism in cancer cells without toxic effects in normal cells remains a great challenge for experimental oncologists.…”

Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer

“…DHA enhances the anticancer drug oxaliplatin-induced autophagic cell death via activating Sestrin 2 and increasing ER stress in CRC cells [ 292 ]. Co-treatment with DHA and vitamin E delta-tocotrienol (Delta-T3) reduces lipid droplet biogenesis and potentiates lipophagy in TNBC MDA-MB-231 cells, resulting in the mitigation of breast cancer malignancy [ 293 ].…”

“…DHA enhances the anticancer drug oxaliplatin-induced autophagic cell death via activating Sestrin 2 and increasing ER stress in CRC cells [292]. Co-treatment with DHA and vitamin E delta-tocotrienol (Delta-T3) reduces lipid droplet biogenesis and potentiates lipophagy in TNBC MDA-MB-231 cells, resulting in the mitigation of breast cancer malignancy [293] Several histone deacetylase inhibitors (HDACIs), such as trichostatin A (TSA), SAHA (also known as vorinostat) and depsipeptide, have been widely studied as cancer therapeutic agents. TSA-induced apoptosis is associated with multiple mechanisms, with the most likely being the modulation of autophagy.…”