Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer.
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ABSTRACT:
SUBMITTER: Loo SY
PROVIDER: S-EPMC8494440 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer.
Loo Ser Yue SY Toh Li Ping LP Xie William Haowei WH Pathak Elina E Tan Wilson W Ma Siming S Lee May Yin MY Shatishwaran S S Yeo Joanna Zhen Zhen JZZ Yuan Ju J Ho Yin Ying YY Peh Esther Kai Lay EKL Muniandy Magendran M Torta Federico F Chan Jack J Tan Tira J TJ Sim Yirong Y Tan Veronique V Tan Benita B Madhukumar Preetha P Yong Wei Sean WS Ong Kong Wee KW Wong Chow Yin CY Tan Puay Hoon PH Yap Yoon Sim YS Deng Lih-Wen LW Dent Rebecca R Foo Roger R Wenk Markus R MR Lee Soo Chin SC Ho Ying Swan YS Lim Elaine Hsuen EH Tam Wai Leong WL
Science advances 20211006 41
Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of ...[more]
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Project description:Background Defects in the renal fatty acid β-oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Qβ-003. In this study, we investigated the potential effectiveness of the PCSK9Qβ-003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low-density lipoprotein receptor+/- male mice fed with a high-cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate-buffered saline group, the Qβ virus-like particles group and the PCSK9Qβ-003 vaccine group. Mice of the PCSK9Qβ-003 group were injected with the PCSK9Qβ-003 vaccine (100 μg/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N-nitro-l-arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Qβ-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in low-density lipoprotein receptor+/- mice with hypercholesterolemia. Compared with the phosphate-buffered saline and Qβ virus-like particles groups, the PCSK9Qβ-003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Qβ-003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Qβ-003 vaccine obviously upregulated the expression of low-density lipoprotein receptor, very-low-density lipoprotein receptor, sterol-regulatory element binding protein 2, and fatty acid β-oxidation-related factors, and ameliorated renal fibrosis-related molecules both in the unilateral ureteral obstruction and N-nitro-l-arginine methyl ester models. Conclusions This study suggested that the PCSK9Qβ-003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid β-oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.
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Project description:Fatty acid oxidation (FAO) has been proven to be an accomplice in tumor progression. Carnitine palmitoyltransferase 1C (CPT1C), a rate-limiting enzyme in FAO, mainly functions to catalyze fatty acid carnitinylation and guarantee subsequent entry into the mitochondria for FAO in colorectal cancer (CRC). Gene expression data and clinical information extracted from The Cancer Genome Atlas (TCGA) database show significantly higher expression of CPT1C in patients with metastatic CRC ( P=0.005). Moreover, overexpression of CPT1C is correlated with worse relapse-free survival in CRC (HR 2.1, P=0.0006), while no statistical significance is indicated for CPT1A and CPT1B. Further experiments demonstrate that downregulation of CPT1C expression leads to a decrease in the FAO rate, suppression of cell proliferation, cell cycle arrest and repression of cell migration in CRC, whereas opposite results are obtained when CPT1C is overexpressed. Furthermore, an FAO inhibitor almost completely reverses the enhanced cell proliferation and migration induced by CPT1C overexpression. In addition, analysis of TCGA data illustrates a positive association between CPT1C expression and HIF1α level, suggesting that CPT1C is a transcriptional target of HIF1α. In conclusion, CPT1C overexpression indicates poor relapse-free survival of patients with CRC, and CPT1C is transcriptionally activated by HIF1α, thereby promoting the proliferation and migration of CRC cells.
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Project description:Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes significantly diminishes in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1, and SCGB3A2. Further, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.
2025-02-25 | GSE284440 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes significantly diminishes in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1, and SCGB3A2. Further, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.
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Project description:Purpose. Experimental data suggest that tumour cells can reversibly transition between epithelial and mesenchymal states (EMT and MET), a phenomenon known as cellular plasticity. The aim of this review was to appraise the clinical evidence for the role of cellular plasticity in prostate cancer (PC) bone metastasis. Methods. An electronic search was performed using PubMed for studies that have examined the differential expression of epithelial, mesenchymal, and stem cell markers in human PC bone metastasis tissues. Results. The review included nineteen studies. More than 60% of the studies used ?20 bone metastasis samples, and there were several sources of heterogeneity between studies. Overall, most stem cell markers analysed, except for CXCR4, were positively expressed in bone metastasis tissues, while the expression of EMT and MET markers was heterogeneous between and within samples. Several EMT and stemness markers that are involved in osteomimicry, such as Notch, Met receptor, and Wnt/? pathway, were highly expressed in bone metastases. Conclusions. Clinical findings support the role of cellular plasticity in PC bone metastasis and suggest that epithelial and mesenchymal states cannot be taken in isolation when targeting PC bone metastasis. The paper also highlights several challenges in the clinical detection of cellular plasticity.
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