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Review
. 2024 Jan-Dec:23:15347354241243024.
doi: 10.1177/15347354241243024.

Molecular Mechanisms Associated with the Inhibitory Role of Long Chain n-3 PUFA in Colorectal Cancer

Abilasha Gayani Jayathilake  1 , Rodney Brain Luwor  2   3 , Kulmira Nurgali  1   2   4 , Xiao Qun Su  1
Affiliations
Review

Molecular Mechanisms Associated with the Inhibitory Role of Long Chain n-3 PUFA in Colorectal Cancer

Abilasha Gayani Jayathilake et al. Integr Cancer Ther. 2024 Jan-Dec.

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related death in the world. Multiple evidence suggests that there is an association between excess fat consumption and the risk of CRC. The long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential for human health, and both in vitro and in vivo studies have shown that these fatty acids can prevent CRC development through various molecular mechanisms. These include the modulation of arachidonic acid (AA) derived prostaglandin synthesis, alteration of growth signaling pathways, arrest of the cell cycle, induction of cell apoptosis, suppression of angiogenesis and modulation of inflammatory response. Human clinical studies found that LC n-3 PUFA combined with chemotherapeutic agents can improve the efficacy of treatment and reduce the dosage of chemotherapy and associated side effects. In this review, we discuss comprehensively the anti-cancer effects of LC n-3 PUFA on CRC, with a main focus on the underlying molecular mechanisms.

Keywords: DHA; EPA; LC n-3 PUFA; colorectal cancer; molecular mechanisms.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Schematic overview of biosynthesis of long chain PUFA and actions of main metabolites from arachidonic acid verse that from EPA. High metabolism of linoleic acid to arachidonic acid contributes to cancer risk and progression through the synthesis of pro-inflammatory and pro-tumor lipid metabolites. High metabolism of α-linolenic acid to EPA and DHA reduces cancer risk and progression through the synthesis of anti-inflammatory and anti-tumor lipid metabolites. Abbreviations: COX1/2, cyclooxygenase 1/2; LOX, lipoxygenase; PGE2/3, prostaglandin E2/E3; LTB4/5, leukotrienes B4/B5; Ras, retrovirus-associated DNA sequences; MEK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; Wnt, Wingless-related integration site; BLT1/BLT2, Leukotriene B4 receptor, NF-ĸB, nuclear factor kappa-light-chian-enhancer of activated B cells; FADS1/2, Fatty acid desaturase 1/2; ELOV5, fatty acid elongase 5.
Figure 2.
Figure 2.
_targeted signaling pathways by LC n-3 PUFA in relation to the death of cancer cells. (A) represents the inhibition of EGFR activation and the inhibition of its downstream signaling pathways. (B) represents the suppression of phosphorylation of the RAS/MEK pathway. (C) shows the inhibition of the PI3K/AKT/mTOR signaling cascade. Phosphorylated AKT activates mTOR, which further activates the transcription factors necessary for the transcription of genes essential for cell proliferation, metastasis, angiogenesis. (D) shows an intrinsic apoptosis pathway that activates through the up-regulation of pro-apoptotic Bcl-2 protein and down-regulation of anti-apoptotic Bcl-2 protein that leads to alteration of MMP to release cytochrome c. Cytochrome c forms an apoptosome with the binding of Apaf and caspase-9 to further activate caspase-3 to induce apoptosis. (E) represents the intrinsic apoptosis pathway through the endoplasmic reticulum. (F) represents the extrinsic pathway of apoptosis showing Eas/FasL interaction and DISC formation leading to caspase-8 activation. (G) represents the suppression of NF-қB that upregulates the transcription of genes involved in inflammation, angiogenesis, and metastasis. (H) represents all phases of the cell cycle together with its cyclin and CDKs. The LC n-3 PUFA suppress the cell cycle by alteration of cyclin and CDKs. Abbreviations: EGFR, epidermal growth factor receptor; EGF, epidermal growth factor; P, phosphorylation; RAS, retrovirus-associated DNA sequences; RAF, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PI3K, Phosphatidylinositol-3-kinase; AKT, threonine-protein kinase; mTOR, Mammalian _target of rapamycin; Bcl-2, B-cell lymphoma-2; BAX, Bcl-2 Associated X-protein; BAK, Bcl-2 Antagonist/Killer; tBid, truncated Bid; Puma, p53 upregulated modulator of apoptosis; MCL-1, myeloid cell leukemia-1; Bcl-xL, B-cell lymphoma-extra-large; BIM, Proapoptotic Bcl-2 homology 3-only protein; FADD, Fas-associated death domain protein; TRAIL-1 /2, Tumor necrosis factor-related apoptosis-inducing ligand receptor 1 /2; FAS, Fas Cell Surface Death Receptor; DISC, death-inducting signaling complex; CDK, cyclin-dependent kinase; G1, gap 1/growth 1; G2, gap-2/growth 2; M, mitosis; S, Synthesis Phase; DNA, deoxyribonucleic acid; JNK, Jun N-terminal kinase; NF-ĸB, nuclear factor kappa-light-chain-enhancer of activated B cells; COX-2, cyclooxygenase-2; PGE-2, prostaglandin E2; iNOS, inducible nitric oxide synthase; NO, nitric oxide; BH3, canonical mitochondrial apoptosis.
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