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CPT1A, LKB1, and AMPKα-1 siRNAs decrease CPT1 enzyme activity in MCF-7 and MDA-MB-231 breast cancer cells. CPT1 enzyme activity assays were performed on cells transiently transfected with siRNAs targeting CPT1A, LKB1, or AMPKα-1. A) In 184B5 cells, treatment with CPT1A siRNA decreased enzyme activity by 30% relative to vehicle (p < 0.05). B) CPT1 enzyme activity was decreased by 17, 22, and 30% relative to vehicle in MCF-7 cells treated with CPT1A, LKB1, and AMPKα-1 siRNAs, respectively (p < 0.05). C) In MDA-MB-231 cells, knock-down of CPT1A resulted in a 24% reduction in enzyme activity relative to vehicle (p < 0.05), and LKB1 and AMPKα-1 siRNAs led to 29 and 23% reductions relative to vehicle, respectively (p < 0.05). Different letters represent statistical differences between groups. Results represent the mean ± SEM of three independent experiments.
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Mammary carcinomas have been associated with a high-fat diet, and the rate of breast cancer in overweight post-menopausal women is up to 50% higher than in their normal-weight counterparts. Epidemiological studies suggest that prolactin (PRL) plays a role in the progression of breast cancer. The current study examined breast cancer as a metabolic d...
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Currently it is unclear whether lipid accumulation occurs in a particular sequence and its relationship with whole body insulin resistance (IR). This study aimed to answer this question.
Male Sprague-Dawley (SD) rats were fed on a normal or a high-fat diet for 20 weeks. Serum triglycerides (TG), serum free fatty acids (FFA), fasting plasma glucose...
Citations
... Mitochondrial dysfunction including genetic or metabolic alterations may lead to an imbalance in lipid homeostasis and eventually to cancer. While in some, mitochondrial fatty acid oxidation is stimulated as energy supplying source in cases of prostate cancer [65] and breast cancer [66,67], and in some others, mitochondrial CPT1 activity is reduced [68] and contributes to an imbalance in the energy homeostasis state favoring fatty acid synthase (FASN) activity [69] leading to tumor formation [70]. To overcome this fatty acids-driven lipotoxicity, cancer cells initiate a cross-signaling between the tyrosine kinase human epidermal growth factor receptor (HER2) and FASN [71,72]. ...
... The next step involves the transport of long-chain fatty acids (e.g., palmitate) into the intermembrane space and the subsequent conversion of acylcarnitine back to CoA for β-oxidation, which is catalysed by CPT2, localised to the inner membrane [8][9][10]. Several studies show that high CPT1 levels are closely associated with tumour progression in breast cancer, making it an important target for pharmacotherapy [11][12][13][14]. Indeed, these studies suggest that inhibition of CPT1A reduces proliferation rates, decreases cancer cell chemoresistance, and increases apoptosis. ...
Canine mammary tumours (CMTs) are the most common cancer in intact female dogs. In addition to surgery, additional targeted and non-targeted therapies may offer survival benefits to these patients. Therefore, exploring new treatments for CMT is a promising area in veterinary oncology. CMT cells have an altered lipid metabolism and use the oxidation of fatty acids for their energy needs. Here we investigated the tumoricidal effects of teglicar, a reversible inhibitor of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid import into mitochondria, on two CMT cells, P114 and CMT-U229. Viability and apoptosis were examined in CMT cells using the crystal violet assay, trypan blue assay, and flow cytometry analysis. The expression of mediators of apoptosis signalling (e.g., caspase-9, caspase-8, and caspase-3) was assessed by quantitative real-time polymerase chain reaction and western blot analyses. Teglicar was able to decrease cell viability and induce apoptosis in P114 and CMT-U229 cells. At the molecular level, the effect of teglicar was associated with an upregulation of the mRNA expression levels of caspase-9, caspase-8, and caspase-3 and an increase in their protein levels. In summary, our results show that teglicar has a potential effect against CMTs through the induction of apoptotic cell death, making it a promising therapeutic agent against CMTs.
... Fatty acid oxidation (FAO): FAO is the mitochondrial aerobic process of breaking down fatty acid (FA) into acetyl-CoA-units [123]. Overexpression of carnitine palmitoyl transferase I (CPTI), a rate-limiting enzyme of FAO, is associated with breast cancer progression [124][125][126]. FAO contributes to elevated ATP in TNBC and metastasis [127,128], and promotes apoptosis-resistance of TNBC by increasing mitochondrial membrane lipids [129]. ...
Breast cancer is the most frequently diagnosed malignancy worldwide and the leading cause of cancer mortality in women. Despite the recent development of new therapeutics including targeted therapies and immunotherapy, triple-negative breast cancer remains an aggressive form of breast cancer, and thus improved treatments are needed. In recent decades, it has become increasingly clear that breast cancers harbor metabolic plasticity that is controlled by mitochondria. A myriad of studies provide evidence that mitochondria are essential to breast cancer progression. Mitochondria in breast cancers are widely reprogrammed to enhance energy production and biosynthesis of macromolecules required for tumor growth. In this review, we will discuss the current understanding of mitochondrial roles in breast cancers and elucidate why mitochondria are a rational therapeutic target. We will then outline the status of the use of mitochondria-targeting drugs in breast cancers, and highlight ClpP agonists as emerging mitochondria-targeting drugs with a unique mechanism of action. We also illustrate possible drug combination strategies and challenges in the future breast cancer clinic.
... To provide additional evidence, SCD1 gene silencing was performed, leading to an increased level of n-9/n-7 isomer ratio in PC 16:0_16:1, consistent with the results observed after CAY10566 treatment (Fig. 6C). Interestingly, MDA-MB-231 cells have a higher proportion of n-9 isomers in C16:1-containing GPs compared to the other cell lines (Fig. 6D), suggesting that FAO is more active, which is consistent with previous research [52]. Furthermore, the increases of n-9 isomer in C16:1-containing GPs were consistently observed in all human breast cancer cell lines (Fig. 6D). ...
The study of lipid metabolism relies on the characterization of the lipidome, which is quite complex due to the structure variations of the lipid species. New analytical tools have been developed recently for characterizing fine structures of lipids, with C=C location identification as one of the major improvements. In this study, we studied the lipid metabolism reprograming by analyzing glycerol phospholipid compositions in breast cancer cell lines with structural specification extended to the C=C location level. Inhibition of the lipid desaturase, stearoyl-CoA desaturase 1, increased the proportion of n -10 isomers that are produced via an alternative fatty acid desaturase 2 pathway. However, there were different variations of the ratio of n -9/ n -7 isomers in C18:1-containing glycerol phospholipids after stearoyl-CoA desaturase 1 inhibition, showing increased tendency in MCF-7 cells, MDA-MB-468 cells, and BT-474 cells, but decreased tendency in MDA-MB-231 cells. No consistent change of the ratio of n -9/ n -7 isomers was observed in SK-BR-3 cells. This type of heterogeneity in reprogrammed lipid metabolism can be rationalized by considering both lipid desaturation and fatty acid oxidation, highlighting the critical roles of comprehensive lipid analysis in both fundamental and biomedical applications.
... Acyl carnitines are indispensable metabolite hubs for βoxidation of fatty acids, which supply source of energy for cell growth and proliferation 44 . Sex hormones including estradiol and estrogen were showed to inhibit β-oxidation through action on carnitine palmitoyltransferase 45,46 . Although high dose of L-carnitine administration has been reported to cause diarrhea in healthy individuals 47 , it is unclear the intertwined links between carnitine metabolism mediated by sex hormones and the diarrhea induced during chemoradiotherapy. ...
Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). Therapeutic efficacy of nCRT is significantly affected by treatment-induced diarrhea and hematologic toxicities. Metabolic alternations in cancer therapy are key determinants to therapeutic toxicities and responses, but exploration in large-scale clinical studies remains limited. Here, we analyze 743 serum samples from 165 LARC patients recruited in a phase III clinical study using untargeted metabolomics and identify responsive metabolic traits over the course of nCRT. Pre-therapeutic serum metabolites successfully predict the chances of diarrhea and hematologic toxicities during nCRT. Particularly, levels of acyl carnitines are linked to sex disparity in nCRT-induced diarrhea. Finally, we show that differences in phenylalanine metabolism and essential amino acid metabolism may underlie distinct therapeutic responses of nCRT. This study illustrates the metabolic dynamics over the course of nCRT and provides potential to guide personalized nCRT treatment using responsive metabolic traits. Neoadjuvant chemoradiotherapy is the standard treatment for patients with locally advanced rectal cancer, however, response can be limited by development of toxicities. Here, the authors conducted metabolomics on patients with locally advanced rectal cancer enrolled in a phase III clinical study and identify serum metabolites associated with treatment response.
... These results agree with previous data that highlight the importance of the β-oxidation pathway for the correct decidualization of ESC [17]. In addition, it has been described that in breast cancer cells prolactin increases the expression and the activity of CPTA1 in relation to normal cells [21]. The mammary gland and the endometrium are both hormone-responsive tissue, that share also the expression of PRL receptors. ...
The differentiation of endometrial stromal cells, named decidualization, is essential for the proper formation of the materno-fetal interphase. One important feature of decidualization is the increased glucose consumption and its utilization by endometrial cells to produce energy. Besides glucose, fatty acids are another important energy source for living cells and it has been described that endometrial stromal cells rely on the proper function of the oxidation of fatty acids for the correct decidualization. It is, however, unknown whether the turn-over of fatty acid degradation is modified during decidualization. Furthermore, it is also unknown how the final products of glucose and fatty acid catabolism are related to the function of the tricarboxylic acid cycle for the efficient ATP production. In this study, we evaluated the content levels of different intermediate metabolites and the expression of the key enzymes related to the degradation of glucose and fatty acids during the in vitro decidualization of human endometrial stromal cells. Our results suggest that human endometrial stromal cells undergo energetic metabolic changes during decidualization and that decidualizing and non-decidualizing cells differ in the level of activation of different metabolic pathways and, probably, in the use of intermediate metabolites.
... The mitochondrial fatty acid oxidation (FAO) pathway is activated in tumor cells with high energy demand. The rate-limiting enzyme CPT1 is associated with the outer mitochondrial membrane and regulates energy homeostasis since it is required for fatty acid β-oxidation in mitochondria [47,48]. We unexpectedly observed that LIPG knockdown slightly increased FABP4 mRNA but remarkably enhanced CPT1 mRNA expression. ...
Triple-negative breast cancer (TNBC) cells reprogram their metabolism to provide metabolic flexibility for tumor cell growth and survival in the tumor microenvironment. While our previous findings indicated that endothelial lipase (EL/LIPG) is a hallmark of TNBC, the precise mechanism through which LIPG instigates TNBC metabolism remains undefined. Here, we report that the expression of LIPG is associated with long non-coding RNA DANCR and positively correlates with gene signatures of mitochondrial metabolism-oxidative phosphorylation (OXPHOS). DANCR binds to LIPG, enabling tumor cells to maintain LIPG protein stability and OXPHOS. As one mechanism of LIPG in the regulation of tumor cell oxidative metabolism, LIPG mediates histone deacetylase 6 (HDAC6) and histone acetylation, which contribute to changes in IL-6 and fatty acid synthesis gene expression. Finally, aided by a relaxed docking approach, we discovered a new LIPG inhibitor, cynaroside, that effectively suppressed the enzyme activity and DANCR in TNBC cells. Treatment with cynaroside inhibited the OXPHOS phenotype of TNBC cells, which severely impaired tumor formation. Taken together, our study provides mechanistic insights into the LIPG modulation of mitochondrial metabolism in TNBC and a proof-of-concept that targeting LIPG is a promising new therapeutic strategy for the treatment of TNBC.
... Up-regulation of CPT2 transcripts at the morula stage [37] was coincident with increased oxygen uptake [38], fatty acid oxidation [39]. In addition, increased transcript abundance of candidate beta-oxidation regulator (CPT1B) was associated with the rate of fatty acid oxidation and survival of cancer cells [40] that coupled with apoptosis inhibition [41]. ...
l-carnitine is a well-known an antioxidant that enhanced lipid metabolism. Therefore, this study investigated the influence of supplementing l-carnitine (LC) to in vitro culture medium on preimplantation development, quality, cryotolerance and transcription profile of candidate genes. Following in vitro fertilization, embryos at zygote stage were cultured with medium supplemented with LC at 1.5 mM and fetal calf serum (FCS) at 0, 2.5, 5, 7.5 and 10% of the CR1-aa culture media. Intracellular quality of produced embryos was measured using different fluorescent stains that measured reactive oxygen species (ROS), lipid and mitochondria intensities. In addition, total cell number and total apoptotic cells were counted per embryo. Quantitative expression of candidate genes was conducted to find out molecular response of embryos after treatment. Moreover, vitrification was done at day 8 of preimplantation development to evaluate post-thaw embryo viability. The results indicated improved blastocyst formation rate at day 8 of preimplantation development (day zero = day of IVF) when embryos cultured with LC supplementation at low FCS at levels of 2.5% (35.3%) and 5% (34.7%) compared to control (25.9%), LC + FCS 7.5% (26.5%) and LC + FCS 10% (28.1%) groups. The total number of blastocyst cells that were cultured with LC + FCS 2.5% and LC + FCS 5% was increased and the number of dead cells (apoptotic) was decreased compared to control counterparts. Intracellular mitochondria activity was enhanced and resulted in reduction of cytoplasmic lipid in embryos treated with LC + FCS 2.5% and LC + FCS 5% compared with other experimental embryo groups. In addition, intracellular reactive oxygen species level was reduced in LC + FCS 2.5%, LC + FCS 5% and LC + FCS 7.5% compared to control and LC + FCS 10% groups. The expression profile of genes regulating embryo quality (BCL2), metabolic activity (GLUT1, CPT2 and TFAM), lipolysis (LIPE, AMPKa1 and ACCα), resistance to stress (SOD2) and ability to induce pregnancy (IFNt) was up-regulated under low FCS (2.5% and 5%) combined with LC supplementation. On the other hand, genes regulating lipogenesis were down-regulated (ACSL3 and S1PR). It can be concluded that LC is an efficient culture media supplement when added with FCS at 2.5 and 5% which improved blastocyst development rate and quality. These improvements are due to enhanced utilization of intracellular embryo lipid that subsequently increased cryotolerance through orchestrating genes involved in various activities of bovine embryos.
... Carnitine Palmitoyltransferase I Carnitine palmitoyltransferase I (CPTI) converts fatty acyl-CoA to its corresponding fatty-acyl carnitine to be transported into the mitochondrial matrix [120]. Several studies have implicated CPTI in tumorigenesis, with breast [60,61] and ovarian [63] cancers displaying elevated mRNA levels ( Table 1). CPTI expression is higher in more aggressive breast cancer subtypes, such as triple-negative breast cancer (TNBC), than in less aggressive ones [61], suggesting a role of CPTI in determining the aggressiveness of gynaecological cancers. ...
... Several studies have implicated CPTI in tumorigenesis, with breast [60,61] and ovarian [63] cancers displaying elevated mRNA levels ( Table 1). CPTI expression is higher in more aggressive breast cancer subtypes, such as triple-negative breast cancer (TNBC), than in less aggressive ones [61], suggesting a role of CPTI in determining the aggressiveness of gynaecological cancers. Supporting this, CPTI overexpression is associated with poor prognosis, as shown in ovarian cancer patients [63]. ...
Gynaecological cancers are among the leading causes of cancer-related death among women worldwide. Cancer cells undergo metabolic reprogramming to sustain the production of energy and macromolecules required for cell growth, division and survival. Emerging evidence has provided significant insights into the integral role of fatty acids on tumourigenesis, but the metabolic role of high endogenous oestrogen levels and increased gynaecological cancer risks, notably in obesity, is less understood. This is becoming a renewed research interest, given the recently established association between obesity and incidence of many gynaecological cancers, including breast, ovarian, cervical and endometrial cancers. This review article, hence, comprehensively discusses how FA metabolism is altered in these gynaecological cancers, highlighting the emerging role of oestradiol on the actions of key regulatory enzymes of lipid metabolism, either directly through its classical ER pathways, or indirectly via the IGIFR pathway. Given the dramatic rise in obesity and parallel increase in the prevalence of gynaecological cancers among premenopausal women, further clarifications of the complex mechanisms underpinning gynaecological cancers are needed to inform future prevention efforts. Hence, in our review, we also highlight opportunities where metabolic dependencies can be exploited as viable therapeutic targets for these hormone-responsive cancers.
... Acetylcarnitine is an acetylated form of L-carnitine, mainly used for energy production by transporting activated longchain fatty acids from the cytosol into mitochondria (Lee et al., 2020). Long-chain acetylcarnitine was reported to be an essential source of energy production in cancer cells (Linher-Melville et al., 2011). In recent years, acetylcarnitine has attracted much attention in tumor research (Fong et al., 2011). ...
Background
Intravenous leiomyomatosis (IVL) is a rare estrogen-dependent neoplasm. However, identifiable and reliable biomarkers are still not available for clinical application, especially for the diagnosis and prognosis of the disease.Methods
In the present study, 30 patients with IVL and 30 healthy controls were recruited. Serum samples were isolated from these participants for further high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis to study metabolomics alterations and identify differentially expressed metabolites based on orthogonal partial least-squares discriminant analysis (OPLS-DA). Subsequently, lasso regression analysis and a generalized linear regression model were applied to screen out hub metabolites associated with the progression of IVL.ResultsFirst, 16 metabolites in the positive ion mode were determined from the 240 identifiable metabolites at the superclass level, with ten metabolites upregulated in the IVL group and the remaining six metabolites downregulated. Our data further proved that four metabolites [hypoxanthine, acetylcarnitine, glycerophosphocholine, and hydrocortisone (cortisol)] were closely related to the oncogenesis of IVL. Hypoxanthine and glycerophosphocholine might function as protective factors in the development of IVL (OR = 0.19 or 0.02, respectively). Nevertheless, acetylcarnitine and hydrocortisone (cortisol), especially the former, might serve as risk indicators for the disease to promote the development or recurrence of IVL (OR = 18.16 or 2.10, respectively). The predictive accuracy of these hub metabolites was further validated by the multi-class receiver operator characteristic curve analysis (ROC) with the Scikit-learn algorithms.Conclusion
Four hub metabolites were finally determined via comprehensive bioinformatics analysis, and these substances could potentially serve as novel biomarkers in predicting the prognosis or progression of IVL.
