Abstract
Fatty acid uptake and metabolism are often dysregulated in cancer cells. Fatty acid activation is a critical step that allows these biomolecules to enter cellular metabolic pathways such as mitochondrial β-oxidation for ATP generation or the lipogenic routes that generate bioactive lipids such as the inositol phospholipids. Fatty acid activation by the addition of coenzyme A is catalysed by a family of enzymes called the acyl CoA synthetase ligases (ACSL). Furthermore, enhanced expression of particular ACSL isoforms, such as ACSL4, is a feature of some more aggressive cancers and may contribute to the oncogenic phenotype. This study focuses on ACSL3 and ACSL4, closely related structural homologues that preferentially activate palmitate and arachidonate fatty acids, respectively. In this study, immunohistochemical screening of multiple soft tissue tumour arrays revealed that ACSL3 and ACSL4 were highly, but differentially, expressed in a subset of leiomyosarcomas, fibrosarcomas and rhabdomyosarcomas, with consistent cytoplasmic and granular stainings of tumour cells. The intracellular localisations of endogenously expressed ACSL3 and ACSL4 were further investigated by detailed subcellular fractionation analyses of HT1080 fibrosarcoma and MCF-7 breast cancer cells. ACSL3 distribution closely overlapped with proteins involved in trafficking from the trans-Golgi network and endosomes. In contrast, the ACSL4 localisation pattern more closely followed that of calnexin which is an endoplasmic reticulum resident chaperone. Confocal immunofluorescence imaging of MCF-7 cells confirmed the intracellular localisations of both enzymes. These observations reveal new information regarding the compartmentation of fatty acid metabolism in cancer cells.
Highlights
Altered cellular energetics is a recently proposed hallmark of cancer [1]
In light of recent demonstrations that ACSL4 may be involved in channelling specific pools of acyl chains to inositol phospholipids and given that ACSL3 could potentially be important in this regard, we sought to establish the subcellular distributions of these fatty acid-activating enzymes relative to key enzymes involved in inositol phospholipid metabolism and signalling
Given that ACSL4 has been found necessary for ferroptosis in breast cancer cells, we report our findings regarding the subcellular targeting of endogenously expressed ACSL3 and ACSL4 in MCF7 breast cancer cells
Summary
Altered cellular energetics is a recently proposed hallmark of cancer [1]. In this context, upregulated lipid metabolism is one of the most striking metabolic changes observed in many tumour cells [2]. In order to understand more completely how fatty acid metabolism is compartmentalised in cancer cells, it is first necessary to determine the organelle-association patterns for endogenously ACSL3 and ACSL4 in different cancer subtypes and cell lines. Upregulated ACSL3-dependent fatty acid metabolism, and in particular augmented β-oxidation of ACSL3-derived lipid products, has recently been identified as a key determinant underlying the oncogenicity of lung tumour cells with a mutant KRAS driver mutation [19, 20]. In light of recent demonstrations that ACSL4 may be involved in channelling specific pools of acyl chains to inositol phospholipids and given that ACSL3 could potentially be important in this regard, we sought to establish the subcellular distributions of these fatty acid-activating enzymes relative to key enzymes involved in inositol phospholipid metabolism and signalling. Given that ACSL4 has been found necessary for ferroptosis in breast cancer cells, we report our findings regarding the subcellular targeting of endogenously expressed ACSL3 and ACSL4 in MCF7 breast cancer cells
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