DHA induces apoptosis of human malignant breast cancer tissues by the TLR‑4/PPAR‑α pathways

Geng, Lihua; Zhou, Wei; Liu, Bing; Wang, Xinyun; Chen, Bin

doi:10.3892/ol.2017.7702

Cited by 24 publications

(34 citation statements)

References 62 publications

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“…To determine whether CBD and DHA also have opposing effects in a cellular context, we quantified the effect of CBD and DHA on cholesterol-dependent apoptosis. DHA treatment induced apoptosis in both HEK293T and SK-N-BE(2) cells in a dose dependent manner (Figure S6D and S6E), consistent with previous studies (Geng et al, 2018;Serini et al, 2008;Shin et al, 2013;Sun et al, 2013). Importantly, this DHA-induced apoptosis proved to be cholesterol dependent, as simultaneous treatment with DHA and the cholesterol sequestering agent, MBCD, delayed apoptosis in HEK293T cells, and fully rescued apoptosis in SK-N-BE(2) cells (Figure S6D and S6E).…”

Section: Cbd Incorporates Into Membrane Compartments Altering Cholestsupporting

confidence: 91%

Multi-Omic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines

Guard

Chapnick

Ebmeier

et al. 2020

Preprint

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Cannabidiol (CBD) is FDA-approved for treatment of drug-intractable forms of pediatric epilepsy, yet the mechanisms that underlie its efficacy remain unclear. Myriad protein targets of CBD have been reported, suggesting a pleiotropic pharmacology. Here, we report a systems-level analysis of CBD action in human cell lines using temporallyresolved multi-omic profiling and biosensor screening. CDB treatment resulted in a chronic rise in cytosolic calcium and activated AMPK signaling within two hours. Subcellular profiling of proteins, metabolites, and mRNA transcripts identified CBDdependent activation of cholesterol biosynthesis, transport and storage. We found that CBD incorporates into cellular membranes, alters cholesterol chemical activity, and increases lipid order. CBD-induced apoptosis in multiple human cell lines was rescued by inhibition of cholesterol synthesis, and potentiated by compounds that disrupt cholesterol trafficking and storage. Our data point to pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.

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Section: Cbd Incorporates Into Membrane Compartments Altering Cholestsupporting

confidence: 91%

Multi-Omic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines

Guard

Chapnick

Ebmeier

et al. 2020

Preprint

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“…More specifically for breast cancer, several intracellular targets have been identified as being involved in the DHA effect, among which the PKB/akt, and p53 pathways and increased caspase activity (reviewed in [18,23]). Additional mechanisms involved in the pro-apoptotic effect of DHA in breast cancer cells include, but are not limited to, decreased Erk activity [28,29], increased Bax pro-apoptotic enzyme levels or activity and decreased Bcl-XL, increased death receptors (DR-4, TRAIL, and Fas) expression and mitochondrial release of the caspase activator SMAC/Diablo in the MCF-7 cell line [30], PPAR-α overexpression in breast cancer tissue or cells [31,32], increased expression of the stress-induced growth inhibitor 1 (OSGIN1) and transcription factor NFE2L2 in MCF-7 and Hs578T breast cancer cells [33]. However, DHA also increased the activity of antioxidant enzymes (SOD, CAT, and GPX) in breast cancer tissues [31], suggesting that the anti-/pro-oxidant effects of DHA may be dependent on the cell type and concentration used.…”

Section: Introductionmentioning

confidence: 99%

“…A few studies have shown that diet can affect the metastatic potential of cancer cells known to have a high metastatic phenotype such as breast cancer [35,36]. The anti-invasive effect of DHA, at a concentration ranging from 10 to 100 µM, was highlighted in breast cancer cell lines [31,[37][38][39][40][41][42][43]. Moreover, this anti-metastatic effect is corroborated by in vivo animal studies using fat-1 transgenic mice capable of producing n-3 FA from the n-6 type, leading to abundant n-3 FA with reduced levels of n-6 FA in their organs and tissues, and this was without the need of a dietary n-3 supply [44].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Chénais

Cornec

Dumont

et al. 2020

IJERPH

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Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 12 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.

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“…In breast cancer cells, DHA significantly increased the ratio of cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) levels and promoted the expression of Toll-like receptor 4 (TLR-4) and peroxisome proliferator activated receptor (PPAR)-α, resulting in apoptosis. This study suggested a clinical development of DHA oil in breast cancer treatment [ 50 ]. DHA-induced apoptosis mediated ROS-Akt-mammalian target of rapamycin (mTOR) signaling in prostate cancer cells [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Docoxahexaenoic Acid Induces Apoptosis of Pancreatic Cancer Cells by Suppressing Activation of STAT3 and NF-κB

2018

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The ω3-polyunsaturated fatty acid docosahexenoic acid (DHA) is known to induce apoptosis of cancer cells. In this study, DHA was shown to reduce viability of pancreatic cancer cells (PANC-1) by inducing DNA fragmentation, activating caspase-3, and increasing the ratio of Bax/Bcl-2. To determine the DHA mechanism of action, the impact of DHA on the activation of the key signaling proteins epidermal growth factor receptor (EGFR), signal transducer and activator of transcription factor 3 (STAT3), nuclear transcription factor-κB (NF-κB), and IκBα in PANC-1 cells was probed. The observed DHA suppression of NF-κB DNA-binding activity was found to result from reduced IκBα phosphorylation. The observed DHA-induced suppression of STAT3 activation was found to be the result of suppressed EGFR activation, which derives from the inhibitory effect of DHA on the integrity of localization of EGFR to cell membrane lipid rafts. Since the activation of STAT3 and NF-κB mediates the expression of survival genes cyclin D1 and survivin, DHA induced apoptosis by suppressing the STAT3/NF-κB-cyclin D1/survivin axis. These results support the proposal that DHA-induced apoptosis of pancreatic cells occurs via disruption of key pro-cell survival signaling pathways. We suggest that the consumption of DHA-enriched foods could decrease the incidence of pancreatic cancer.

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DHA induces apoptosis of human malignant breast cancer tissues by the TLR‑4/PPAR‑α pathways

Cited by 24 publications

References 62 publications

Multi-Omic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines

Multi-Omic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines

Transcriptomic Response of Breast Cancer Cells MDA-MB-231 to Docosahexaenoic Acid: Downregulation of Lipid and Cholesterol Metabolism Genes and Upregulation of Genes of the Pro-Apoptotic ER-Stress Pathway

Docoxahexaenoic Acid Induces Apoptosis of Pancreatic Cancer Cells by Suppressing Activation of STAT3 and NF-κB

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