17β-estradiol-induced ACSL4 protein expression promotes an invasive phenotype in estrogen receptor positive mammary carcinoma cells

Belkaid, Anissa; Ouellette, Rodney J.; Surette, Marc E.

doi:10.1093/carcin/bgx020

Cited by 52 publications

(41 citation statements)

References 42 publications

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“…Among the five isoforms of ACSL, ACSL4 located in peroxisomes has substrate specificity for polyunsaturated fatty acids C20:4 and C20:5, whereas ACSL1 and ACSL5 have a preference for long chain saturated and unsaturated fatty acids of 16 to 20 carbons. ACLS4 is known to be involved in steroidogenesis by regulating the arachidonate level and is closely linked to inflammation, eicosanoid synthesis, and tumourigenesis . Because ACSL4 plays a major role in maintaining lipid homeostasis, dysfunction or dysregulation of ACLS4 could result in severe metabolic disorders.…”

Section: Discussionmentioning

confidence: 99%

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Suppression of ABCD2 dysregulates lipid metabolism via dysregulation of miR‐141:ACSL4 in human osteoarthritis

Park

Kim

et al. 2018

Cell Biochemistry & Function

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Even though increasing evidence indicates the importance of peroxisomal lipid metabolism in regulating biological and pathological events, its involvement in cartilage development has not been well studied. Here, we identified the importance of peroxisomal function, particularly the functional integrity of ABCD2, in the pathogenesis of osteoarthritis (OA). Knockdown of ABCD2 in OA chondrocytes induced the accumulation of very long chain fatty acids (VLCFAs) and apoptotic cell death. Moreover, knockdown of ABCD2 altered profiles of miRNAs that affect the expression level of ACSL4, a known direct regulator of lipid metabolism. Suppression of ACSL4 in human chondrocytes‐induced VLCFA accumulation, MMP‐13 expression, and apoptotic cell death. In vivo morph‐down of the ACSL4 homologue in zebrafish resulted in significant defects in cartilage development and in vivo knockdown of ACSL4 in cartilage tissue of an OA model mice promoted severe cartilage degradation. In summary, to the best of our knowledge, this is the first report suggesting that the regulatory network among peroxisomal ABCD2:ACSL4:VLCFA serves as a novel regulator of cartilage homeostasis, and these data may provide novel insights into the role of peroxisomal fatty acid metabolism in pathogenesis of human OA. Significance of the study Our study indicates that peroxisomal dysfunction is closely related to OA pathogenesis. Particularly, the functional integrity of ABCD2 may play an important role in OA pathogenesis via the accumulation of VLCFAs and stimulation of apoptotic death through altering profiles of miRNAs that target ACSL4. Our findings suggest that targeting the regulatory network among the peroxisomal ABCD2:ACSL4:VLCFA axis may provide a new potential therapeutic strategy for OA pathogenesis.

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Section: Discussionmentioning

confidence: 99%

“…ACLS4 is known to be involved in steroidogenesis by regulating the arachidonate level 32 and is closely linked to inflammation, 33 eicosanoid synthesis, 34 and tumourigenesis. 35…”

Section: Discussionmentioning

confidence: 99%

Suppression of ABCD2 dysregulates lipid metabolism via dysregulation of miR‐141:ACSL4 in human osteoarthritis

Park

Kim

et al. 2018

Cell Biochemistry & Function

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“…Fatty acid AA treatment could enhance ACSL4 protein ubiquitination and shorten its protein half-life in HepG2 cells via a negative feedback loop (42), as AA is the preferred substrate of ACSL4. By contrast, in breast cancer, the hormone 17β-estradiol extended the half-life of the ACSL4 protein, and subsequently increased cellular uptake of AA and eicosapentaenoic acid (43). This 17β-estradiol-mediated ACSL4 upregulation was found to be essential for the invasiveness of estrogen receptor-expressing breast cancer cells.…”

Section: Molecular Mechanisms To Deregulate Acsl Expression In Cancermentioning

confidence: 91%

“…Several studies highlighted that ACSLs stimulated proliferation in cancer cells. Knockdown of ACSL1, ACSL3 or ACSL4 independently decreased cell proliferation and anchorage-independent growth in multiple cancer cells and xenograft tumor growth in nude mice (11,21,31,43). By contrast, forced overexpression of these ACSLs increased cell proliferation and tumor growth (15,20,24,46,47).…”

Section: Effects Of Acsls On Carcinogenesis and Cancer Developmentmentioning

confidence: 99%

“…Cancer cell invasion and migration are characteristic for cancer progression, recurrence and metastasis. Accumulating data have shown that ACSL1 and ACSL4 could promote cancer cell invasion and migration in breast and prostate cancer cells (20,24,37,43). The common epithelial-mesenchymal transition (EMT) contributes to their actions in cell migration and invasion.…”

Section: Acsls and Deregulated Cancer Metabolismmentioning

confidence: 99%

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Fatty acid activation in carcinogenesis and cancer development: Essential roles of long‑chain acyl‑CoA synthetases (Review)

et al. 2018

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The significance of fatty acid metabolism in cancer initiation and development is increasingly accepted by scientists and the public due to the high prevalence of overweight and obese individuals. Fatty acids have different turnovers in the body: Either breakdown into acetyl-CoA to aid ATP generation through catabolic metabolism or incorporation into triacylglycerol and phospholipid through anabolic metabolism. However, these two distinct pathways require a common initial step known as fatty acid activation. Long-chain acyl-CoA synthetases (ACSLs), which are responsible for activation of the most abundant long-chain fatty acids, are commonly deregulated in cancer. This deregulation is also associated with poor survival in patients with cancer. Fatty acids physiologically regulate ACSL expression, but cancer cells could hijack certain involved regulatory mechanisms to deregulate ACSLs. Among the five family isoforms, ACSL1 and ACSL4 are able to promote ungoverned cell growth, facilitate tumor invasion and evade programmed cell death, while ACSL3 may have relatively complex functions in different types of cancer. Notably, ACSL4 is also essential for the induction of ferroptosis (another form of programmed cell death) by facilitating arachidonic acid oxidation, which makes the enzyme a desirable cancer target. The present review thus evaluates the functions of deregulated ACSLs in cancer, the possible molecular mechanisms involved and the chemotherapeutic potentials to target ACSLs. A better understanding of the pathological effects of ACSLs in cancer and the involved molecular mechanisms will aid in delineating the exact role of fatty acid metabolism in cancer and designing precise cancer prevention and treatment strategies.

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Lipid droplets provide metabolic flexibility for cancer progression

Safi,

Menéndez,

Pol

2024

FEBS Letters

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A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid‐derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD‐resident proteins (perilipins, lipases, and acyl‐CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.

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17β-estradiol-induced ACSL4 protein expression promotes an invasive phenotype in estrogen receptor positive mammary carcinoma cells

Cited by 52 publications

References 42 publications

Suppression of ABCD2 dysregulates lipid metabolism via dysregulation of miR‐141:ACSL4 in human osteoarthritis

Suppression of ABCD2 dysregulates lipid metabolism via dysregulation of miR‐141:ACSL4 in human osteoarthritis

Fatty acid activation in carcinogenesis and cancer development: Essential roles of long‑chain acyl‑CoA synthetases (Review)

Lipid droplets provide metabolic flexibility for cancer progression

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