Illustrates the apoptosis mechanisms triggered by DHA

Illustrates the apoptosis mechanisms triggered by DHA. (A) DHA induces modifications in the plasma membrane environment through various pathways. (1) It increases the expression of SDC-1 via PPARγ, (2) inhibits the Akt-mTOR axis by upregulating PPARγ and PTEN, downregulates the Akt/NFκB cell survival axis, (3) EGFR/STAT3/cyclin D1/survivin and (4) NF-κB/IκBα/cyclin D1/survivin pathways, (5) activates the ERK/JNK/p38 axis, stimulates AMPK, and downregulates the PI3K/Akt pathway. (6) EPA also leads to increased ROS production, activates the PI3K/Akt/Nrf2 signaling pathway, and induces the expression of OSGIN1. The downregulation of antioxidant enzymes such as CAT, GSH, and SOD contributes to the accumulation of intracellular ROS. Furthermore, (7) EPA activates ER stress through the expression of XBP1, PERK, ATF4, ATF6, and phosphorylated EIF2a. These events collectively induce intrinsic apoptosis by triggering the depolarization of the mitochondrial membrane. (8) This is achieved through the downregulation of Bcl-xL and Bcl-2, upregulation of Bax and Bcl-xS, and dimerization of Bax and Bak (9) Consequently, MOMP occurs, leading to the release of Smac/Diablo and cytochrome c from the mitochondria. Activated caspase-9 and -3/7 further execute apoptosis by cleaving PARP and forming DNA adducts. DHA downregulates XIAP, cIAP1, and survivin. (B) On the other hand, (10) DHA triggers the extrinsic pathway of apoptosis by increasing the expression of death receptors such as TRAIL, TNFR, DR4, and FAS. Subsequently, (11) DHA activates FADD and downregulates FLIP. Moreover, DHA sensitizes the apoptotic response to death ligands such as TNF-α, FAS antibody, and TRAIL. Additionally, (12) DHA induces nuclear accumulation of Foxo3a, which binds to the miR-21 promoter, leading to its transcriptional repression and increased TNFα mRNA levels. These events ultimately activate caspase 8 and executioner caspases, promoting apoptosis. (C) (13) Both EPA and DHA demonstrate crosstalk between the intrinsic and extrinsic apoptotic pathways through tBid. These findings highlight the multifaceted apoptotic mechanisms induced by DHA, involving both direct and indirect pathways, and emphasize its potential as a safe and effective option for cancer treatment. DHA: Docosahexaenoic acid. SDC-1: Syndecan-1. PPARγ: Peroxisome proliferator-activated receptor-gamma. Akt: Protein kinase B. mTOR: Mammalian target of rapamycin. PTEN: Phosphatase and tensin homolog. NFκB: Nuclear factor κB. EGFR: Epidermal growth factor receptor. STAT3: Signal transducer and activator of transcription 3. IκBα: Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha. ERK: Extracellular signal-regulated kinase. JNK: c-Jun N-terminal kinase. AMPK: AMP-activated protein kinase. PI3K: Phosphoinositide 3-kinase. ROS: Reactive oxygen species. Nrf2: Nuclear factor erythroid 2-related factor 2. OSGIN1: Oxidative stress-induced growth inhibitor 1. CAT: Catalase. GSH: Glutathione. SOD: Superoxide dismutase. ER: Endoplasmic reticulum. XBP1: X-box-binding protein 1. PERK: Protein kinase R-like endoplasmic reticulum kinase. ATF4: Activating Transcription Factor 4. ATF6: Activating Transcription Factor 6. EIF2a: Eukaryotic translation initiation factor 2A. Bcl-xL: B-cell lymphoma-extra-large. Bcl-2: B-cell lymphoma 2. Bax: Bcl-2 Associated X-protein. Bcl-xS: Bcl-2 homologous short isoform. Bak: Bcl-2 homologous antagonist/killer. MOMP: Mitochondrial outer membrane permeabilization. DNA: Deoxyribonucleic acid. XIAP: X-linked inhibitor of apoptosis protein. cIAP1: Cellular inhibitor of apoptosis protein 1. TRAIL: TNF-related apoptosis inducing ligand. TNFR: Epidermal growth factor receptor. DR4: Death receptor 4. FAS: Fas cell surface death receptor. FADD: FAS-associated death domain protein. FLIP: FLICE inhibitory protein. TNF-α: Tumor necrosis factor-alpha. Foxo3a: Forkhead transcription factor O subfamily member 3a. miR-21: MicroRNA 21. mRNA: Messenger ribonucleic acid. tBid: Truncated form of Bid

Publication

The Involvement of Polyunsaturated Fatty Acids in Apoptosis Mechanisms and Their Implications in Cancer (2023) Mayra Montecillo-Aguado, et al. Int J Mol Sci. 2023 Jul;24(14). Figure: F4. Homo sapiens

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