Fatty acid oxidation: driver of lymph node metastasis

Li, Mao; Xian, Hong-chun; Tang, Ya‐Jie; Liang, Xin‐hua; Tang, Yaling

doi:10.1186/s12935-021-02057-w

Cited by 36 publications

(31 citation statements)

References 122 publications

(136 reference statements)

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“…A recent research work has shown that D-fructose 6-phosphate associated with PFKP may be a prognostic factor for lung cancer (Ganapathy-Kanniappan, 2020). In addition, several studies have suggested that fatty acid oxidation is abnormal in lung cancer cells, and FAO may regulate immune suppression through enabling lymph node metastasis formation (Liu et al, 2020;Li et al, 2021). In our study, we found that KD-FDX1 cells have higher L-palmitoylcarnitine and acylcarnitine levels at the same arachidonic acid (20:4) concentration.…”

Section: Discussionsupporting

confidence: 59%

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

et al. 2021

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Background: Lung cancer has emerged as one of the most common cancers in recent years. The mitochondrial electron transport chain (ETC) is closely connected with metabolic pathways and inflammatory response. However, the influence of ETC-associated genes on the tumor immune response and the pathogenesis of lung cancer is not clear and needs further exploration.Methods: The RNA-sequencing transcriptome and clinical characteristic data of LUAD were downloaded from the Cancer Genome Atlas (TCGA) database. The LASSO algorithm was used to build the risk signature, and the prediction model was evaluated by the survival analysis and receiver operating characteristic curve. We explored the function of FDX1 through flow cytometry, molecular biological methods, and liquid chromatography–tandem mass spectrometry/mass spectrometry (LC–MS/MS).Results: 12 genes (FDX1, FDX2, LOXL2, ASPH, GLRX2, ALDH2, CYCS, AKR1A1, MAOB, RDH16, CYBB, and CYB5A) were selected to build the risk signature, and the risk score was calculated with the coefficients from the LASSO algorithm. The 1-year, 3-year, and 5-year area under the curve (AUC) of ROC curves of the dataset were 0.7, 0.674, and 0.692, respectively. Univariate Cox analysis and multivariate Cox regression analysis indicated that the risk signature is an independent risk factor for LUAD patients. Among these genes, we focused on the FDX1 gene, and we found that knockdown of FDX1 neither inhibited tumor cell growth nor did it induce apoptosis or abnormal cell cycle distribution. But FDX1 could promote the ATP production. Furthermore, our study showed that FDX1 was closely related to the glucose metabolism, fatty acid oxidation, and amino acid metabolism.Conclusion: Collectively, this study provides new clues about carcinogenesis induced by ETC-associated genes in LUAD and paves the way for finding potential targets of LUAD.

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Section: Discussionsupporting

confidence: 59%

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

et al. 2021

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“…LNs are lipid-rich tissues and cancer cells need to utilize lipids to colonize and survive in LNs. FAO is an important way for lipid utilization and is now gradually recognized as a critical driver of LNM (14). Previous studies have reported that increased FAO is involved in enhancing GC cell stemness, chemotherapyresistance and anoikis resistance for omental metastasis (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

“…To form metastasis in LNs, cancer cells must undergo metabolic reprogramming to successfully colonize and survive in an unfavorable microenvironment. Due to the lipid-rich property of LNs, the metabolic adaption of lymphatic metastatic cancer cells is more likely associated with fatty acid metabolism ( 14 ). It has been demonstrated that melanoma cells formed LNM depending on fatty acid oxidation (FAO) ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Exosomal CD44 Transmits Lymph Node Metastatic Capacity Between Gastric Cancer Cells via YAP-CPT1A-Mediated FAO Reprogramming

Wang

Cao

et al. 2022

Front. Oncol.

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BackgroundLymph node metastasis (LNM) commonly occurs in gastric cancer (GC) and is tightly associated with poor prognosis. Exosome-mediated lymphangiogenesis has been considered an important driver of LNM. Whether exosomes directly transmit the LNM phenotype between GC cells and its mechanisms remain elusive.MethodsA highly lymphatic metastatic GC cell line (HGC-27-L) was established by serial passage of parental HGC-27 cells in BALB/c nude mice. The capacities of migration, invasion and LNM; fatty acid oxidation (FAO) levels; and the role of exosome-transferred LNM phenotype were compared among HGC-27-L, HGC-27 and primary GC cell line AGS. Exosomes derived from GC cells and sera were separately isolated using ultracentrifugation and ExoQuick exosome precipitation solution, and were characterized by transmission electron microscopy, Nanosight and western blotting. Transwell assay and LNM models were conducted to evaluate the capacities of migration, invasion and LNM of GC cells in vitro and in vivo. β-oxidation rate and CPT1 activity were measured to assess FAO. CPT1A inhibitor etomoxir was used to determine the role of FAO. Label-free LC-MS/MS proteome analysis screened the differential protein profiling between HGC-27-exosomes and AGS-exosomes. Small interference RNAs and YAP inhibitor verteporfin were used to elucidate the role and mechanism of exosomal CD44. TCGA data analysis, immunochemistry staining and ELISA were performed to analyze the expression correlation and clinical significance of CD44/YAP/CPT1A.ResultsFAO was increased in lymphatic metastatic GC cells and indispensable for sustaining LNM capacity. Lymphatic metastatic GC cell-exosomes conferred LNM capacity on primary GC cells in an FAO-dependent way. Mechanistically, CD44 was identified to be enriched in HGC-27-exosomes and was a critical cargo protein regulating exosome-mediated transmission, possibly by modulating the RhoA/YAP/Prox1/CPT1A signaling axis. Abnormal expression of CD44/YAP/CPT1A in GC tissues was correlated with each other and associated with LNM status, stages, invasion and poor survival. Serum exosomal CD44 concentration was positively correlated with tumor burden in lymph nodes.ConclusionsWe uncovered a novel mechanism: exosomal CD44 transmits LNM capacity between GC cells via YAP-CPT1A-mediated FAO reprogramming from the perspective of exosomes-transferred LNM phenotype. This provides potential therapeutic targets and a non-invasive biomarker for GC patients with LNM.

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“…Unlike other subsets of CD4 + T cells, Treg cells preferentially rely on FAO as a source of energy [9]. FAO is a multistep process that involves the beta‐oxidation of fatty acids in the mitochondria to produce acetyl‐CoA [31]. Several studies have shown that the regulators of FAO process can influence the differentiation of Treg cells.…”

Section: Discussionmentioning

confidence: 99%

Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation

et al. 2022

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Our previous studies have demonstrated that tetrandrine can induce the generation of regulatory T (Treg) cells in vitro and in vivo. But, the underlying mechanism of tetrandrine remains obscure. Naïve CD4+ T cells are isolated from the mesenteric lymph nodes of mice for the differentiation of Treg cells. Flow cytometry is used to detect the frequencies of Treg cells. Non‐targeted metabolomics analysis based on UHPLC‐QTOF/MS is performed to assess the intracellular metabolic profiles. ChIP‐PCR analysis is conducted to detect the level of H3K27ac at Foxp3 promoter and CNS regions. Tetrandrine treatment alters the metabolic profile of Treg cells, and pathway enrichment of differential metabolites mainly involves fatty acid oxidation (FAO). Tetrandrine promotes the mRNA expression of carnitine palmitoyl transferase‐1, and increases the level of acetyl coenzyme A (acetyl‐CoA) and the intracellular oxygen consumption rate. Either CPT1 inhibitor (etomoxir) or siRNA markedly diminishes the promotion of tetrandrine on Treg cell differentiation. Furthermore, tetrandrine enhances the acetylation of H3K27 in the promoter and CNS1 regions of Foxp3 through the acetyl‐CoA derived from FAO. In the mice with collagen‐induced arthritis, tetrandrine also induces Treg cell generation through FAO pathway. In addition, tetrandrine enhances the immunosuppressive function of Treg cells both in vitro and in vivo. The findings indicate that tetrandrine promotes Treg cell differentiation by enhancing FAO‐mediated Foxp3 acetylation, and the CPT1‐mediated FAO can serve as the target for the discovery of novel inducers of Treg cell generation.

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Fatty acid oxidation: driver of lymph node metastasis

Cited by 36 publications

References 122 publications

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

FDX1 can Impact the Prognosis and Mediate the Metabolism of Lung Adenocarcinoma

Exosomal CD44 Transmits Lymph Node Metastatic Capacity Between Gastric Cancer Cells via YAP-CPT1A-Mediated FAO Reprogramming

Tetrandrine, an immunosuppressive alkaloid isolated from Steohania tetrandra S. Moore, induces the generation of Treg cells through enhancing fatty acid oxidation

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