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CPT1A/CPT2 mediated FAO is required for radioresistant breast cancer stem cells. (A) Representative mammospheres formed from MCF7 and RD-BCSCs assessed by immunofluorescence microscopy (cell polarity protein DLG1, HER2, and nucleus are labeled by red, green, and blue respectively). (B) Western blot of FAO enzymes CPT1A, CPT2, and HADHB in MCF7 and RD-BCSCs cells. (C) FAO activity in MCF7 and RD-BCSCs with or without IR treatment for 24 h. (D) Radiation-induced apoptosis measured in RD-BCSCs with or without FAO inhibition (ETX, Etomoxir 200 μM for 48 h). (E) Tumorsphere formation assay of (D). (F) Western blot of phosphorylated ERK in RD-BCSCs treated with ETX, IR or combined. (G) Western blot of CPT1A and CPT2 in RD-BCSCs with CRISPR-mediated CPT1A and CPT2 KO. (H) Radiation induced apoptosis in RD-BCSCs (Control), RD-BCSCs CPT1A KO, and RD-BCSCs CPT2 KO cells. (I) Tumorsphere formation of (H). In (C,D,E,H,I) n = 3; mean ± SD; one-way ANOVA test, *p < 0.05, ***p < 0.001.
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Tumor cells including cancer stem cells (CSCs) resistant to radio- and chemo-therapy must enhance metabolism to meet the extra energy demands to repair and survive such genotoxic conditions. However, such stress-induced adaptive metabolic alternations, especially in cancer cells that survive radiotherapy, remains unresolved. In this study, we found...
Citations
... ECs play an important role in this mechanism, and normal EC function cannot be established without stable metabolism; glucose metabolism has been shown to play a key role in EOPE [29], lipid metabolism plays a key role in ab initio nucleotide synthesis [9], and the role of FAO pathways in the pathogenesis of EOPE has rarely been studied. Pregnant women with PE have impaired lipid metabolism, and CPT1A, a key rate-limiting enzyme in the fatty acid oxidative metabolic pathway, can be used as a metabolic target for antitumor therapy [30]. This molecule plays a key role in angiogenesis, and blocking CPT1A can be a new strategy for blocking angiogenesis [9]; however, whether CPT1A is involved in the pathogenesis of EOPE has not been confirmed. ...
Multiple theories have been proposed to explain the pathogenesis of early-onset preeclampsia (EOPE), and angiogenic dysfunction is an important part of this pathogenesis. Carnitine palmitoyltransferase (CPT1A) is a key rate-limiting enzyme in the metabolic process of fatty acid oxidation (FAO). FAO regulates endothelial cell (EC) proliferation during vascular germination and is also essential for ab initio deoxyribonucleotide synthesis, but its role in EOPE needs to be further elucidated. In the present study, we investigated its functional role in EOPE by targeting the circHIPK3/miR-124-3p/CPT1A axis. In our study, reduced expression of circHIPK3 and CPT1A and increased expression of miR-124-3p in placental tissues from patients with EOPE were associated with EC dysfunction. Here, we confirmed that CPT1A regulates fatty acid oxidative activity, cell proliferation, and tube formation in ECs by regulating FAO. Functionally, knockdown of circHIPK3 suppressed EC angiogenesis by inhibiting CPT1A-mediated fatty acid oxidative activity, which was ameliorated by CPT1A overexpression. In addition, circHIPK3 regulates CPT1A expression by sponging miR-124-3p. Hence, circHIPK3 knockdown reduced fatty acid oxidation in ECs by sponging miR-124-3p in a CPT1A-dependent manner and inhibited EC proliferation and tube formation, which may have led to aberrant angiogenesis in EOPE. Thus, strategies targeting CPT1A-driven FAO may be promising approaches for the treatment of EOPE.
Key messages
Decreased Carnitine palmitoyltransferase (CPT1A) expression in preeclampsia(PE).
CPT1A overexpression promotes FAO activity and tube formation in ECs.
CircHIPK3 can affect CPT1A expression and impaire angiogenesis of EOPE.
CircHIPK3 regulates CPT1A expression by acting as a ceRNA of miR-124-3p in HUVECs.
Confirming the effect of circHIPK3/miR-124-3p/CPT1A axis on EOPE.
Graphical abstract
... Several studies connected aberrant FA oxidation activity to therapeutic resistance in melanoma 22,30 and other cancers 44,45 . For instance, inhibition of FA oxidation enhanced the sensitivity of resistant breast cancer to radiotherapy 46 . Here, we show that inhibition of FA oxidation (by HADH knockdown or etomoxir treatment) efficiently re-sensitized resistant melanoma cells to MAPK therapy, similarly to VARS knockdown. ...
Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.
... Knockdown of CPT1A reduces histone acetylation and improves castration resistance in prostate cancer [34]. Notably, fatty acid oxidation activated by the PGC1α/CEBPB/CPT1A axis exacerbates radioresistance [35]. This suggests to us that CPT1A inhibition may alleviate chemotherapy tolerance of advanced ENKTL-NT. ...
... Fatty acid oxidation acts to feed the tumor growth by increasing ATP and NADPH production to get out of the conditions of metabolic stress [12]. CPT1A, a ratelimiting enzyme in fatty acid oxidation, undergoes upregulation in various tumor types [25][26][27]. Its overexpression in cancer cells can activate fatty acid oxidation, thereby enhancing ATP production. ...
Cervical cancer poses a serious threat to women’s health globally. Our previous studies found that upregulation of TM7SF2, which works as an enzyme involved in the process of cholesterol biosynthesis expression, was highly correlated with cervical cancer. However, the mechanistic basis of TM7SF2 promoting cervical cancer progression via lipid metabolism remains poorly understood. Therefore, quantification of fatty acids and lipid droplets were performed in vitro and in vivo. The protein-protein interaction was verified by Co-IP technique. The mechanism and underlying signaling pathway of TM7SF2 via CPT1A associated lipid metabolism in cervical cancer development were explored using Western blotting, IHC, colony formation, transwell assay, and wound healing assay. This study reported that overexpression of TM7SF2 increased fatty acids content and lipid droplets both in vivo and in vitro experiments. While knockout of TM7SF2 obviously attenuated this process. Moreover, TM7SF2 directly bonded with CPT1A, a key enzyme in fatty acid oxidation, and regulated CPT1A protein expression in cervical cancer cells. Notably, the proliferation and metastasis of cervical cancer cells were elevated when their CPT1A expression was upregulated. Then, rescue assay identified that CPT1A overexpressed could enhance the cell viability and migration in TM7SF2-knockout cells. Furthermore, depletion of TM7SF2 significantly inhibited WNT and β-catenin proteins expression, which was enhanced by CPT1A-overexpressed. The proliferation and migration of cervical cancer cells were reversed in CPT1A-overexpressed cells with the treatment of MSAB, an inhibitor of Wnt/β-Catenin pathway. This study put forward an idea that TM7SF2-induced lipid reprogramming promotes proliferation and migration via CPT1A/Wnt/β-Catenin axis in cervical cancer, underlying the progression of cervical cancer.
... Recent research has pointed to the crucial role of CPT1A mediating FAO as an essential source of NADH, FADH 2 and ATP, providing survival advantage to cancer, as well as being the carbon source for the synthesis of nucleoside metabolic [19][20][21][22]. Meanwhile, CPT1A also shares multiple connections with many other cellular signaling pathways, including c-MYC or AMPK in breast cancer, and promotes cancer proliferation, metastasis or therapeutic resistance through several oncogenic signaling pathways, such as PI3K/AKT/mTOR, VEGF, ERK and Src pathways [23][24][25][26][27][28]. Over-expression of CPT1A correlates strongly with poor patient outcomes of ovarian cancer. ...
Epithelial ovarian cancer (EOC) is a lethal gynecological cancer, of which paclitaxel resistance is the major factor limiting treatment outcomes, and identification of paclitaxel resistance-related genes is arduous. We obtained transcriptomic data from seven paclitaxel-resistant ovarian cancer cell lines and corresponding sensitive cell lines. Define genes significantly up-regulated in at least three resistant cell lines, meanwhile they did not down-regulate in the other resistant cell lines as candidate genes. Candidate genes were then ranked according to the frequencies of significant up-regulation in resistant cell lines, defining genes with the highest rankings as paclitaxel resistance-related genes (PRGs). Patients were grouped based on the median expression of PRGs. The lipid metabolism-related gene set and the oncological gene set were established and took intersections with genes co-upregulated with PRGs, obtaining 229 co-upregulated genes associated with lipid metabolism and tumorigenesis. The PPI network obtained 19 highly confidential synergistic targets (interaction score > 0.7) that directly associated with CPT1A. Finally, FASN and SCD were up-stream substrate provider and competitor of CPT1A, respectively. Western blot and qRT-PCR results confirmed the over-expression of CPT1A, SCD and FASN in the A2780/PTX cell line. The inhibition of CPT1A, SCD and FASN down-regulated cell viability and migration, pharmacological blockade of CPT1A and SCD increased apoptosis rate and paclitaxel sensitivity of A2780/PTX. In summary, our novel bioinformatic methods can overcome difficulties in drug resistance evaluation, providing promising therapeutical strategies for paclitaxel-resistant EOC via taregting lipid metabolism-related enzymes.
... High expression of CPT1A is correlated with the metastasis status of several types of cancers and confers improved migration and invasion abilities to tumor cells. Overexpression of CPT1A has been observed in breast cancer cell lines, tissues, and serum, and its high expression is significantly associated with metastasis and poor prognosis of breast cancer patients (Han et al., 2019;Jariwala et al., 2021;Tan et al., 2021). CPT1A is overexpressed in papillary thyroid cancer (PTC), and its increased expression is correlated with lymph node metastasis, TNM stage, and unfavorable outcome in PTC patients. ...
Metabolic reprogramming frequently occurs in the majority of cancers, wherein fatty acid oxidation (FAO) is usually induced and serves as a compensatory mechanism to improve energy consumption. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO and is widely involved in tumor growth, metastasis, and chemo-/radio-resistance. This review summarizes the most recent advances in understanding the oncogenic roles and mechanisms of CPT1A in tumorigenesis, including in proliferation and tumor growth, invasion and metastasis, and the tumor microenvironment. Importantly, CPT1A has been shown to be a biomarker for diagnosis and prognosis prediction and proved to be a candidate therapeutic target, especially for the treatment of drug- and radiation-resistant tumors. In summary, CPT1A plays remarkable roles in promoting cancer progression and is a potential anticancer therapeutic target.
... Secondly, this study extends the understanding of the role of CPT1A in CRC based on previous studies. CPT1A is a key enzyme involved in FAO, which is frequently overexpressed in various cancers, such as liver cancer, nasopharyngeal carcinoma, breast cancer, ovarian cancer, and so on [37][38][39][40][41]. The high expression of CPT1A may be associated with tumor cell growth, metastasis and resistance, as well as with tumor clinical stage and prognosis [42][43][44]. ...
Colorectal cancer (CRC) is a common and deadly disease of the digestive system, but its targeted therapy is hampered by the lack of reliable and specific biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an urgent and challenging task. Here we report that carnitine palmitoyltransferase 1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC cells and that its inhibition by a secolignan-type compound, 2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial permeability and reduced oxygen consumption and energy metabolism in CRC cells. We also reveal that CPT1A expression correlates with the survival of tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A inhibitor and provides a rationale for its preclinical development as well as a new strategy for CRC targeted therapy.
... The oxidation of fatty acids can provide twice as much energy as carbohydrates, and tumor cells can improve the level of fatty acid oxidation by increasing lipid uptake and fatty acid synthesis In order to improve the efficiency of energy supply [15,16]. Carnitine palmitoyltransferase 1 A (CPT1A) has been reported to be the key enzyme of FAO, and is upregulated in a cancers [17][18][19]. Although targeting key genes involved in lipid metabolism and fatty acid oxidation has been demonstrated to inhibit the progression of solid tumors [20,21], the role of lipid metabolism in lymphangiogenesis and lymph node metastasis in gastric cancer has not been reported. ...
Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.
... Genetic and epigenetic alterations that lead to tamoxifen or endocrine resistance have been widely reported [29][30][31][32][33]. Recent studies have shown that metabolic reprogramming provides survival advantages protecting tumour cells from endocrine therapy-induced death and in turn confers endocrine resistance [34,35]. Previous studies have provided evidence showing that FAO induces paclitaxel resistance [10,21], trastuzumab resistance [15], endoxifen resistance [36], and even radioresistance [37] in BC cells. Moreover, FAO can protect tumour cells from chemotherapyinduced apoptosis by maintaining mitochondrial integrity [22]. ...
Tamoxifen-based endocrine therapy remains a major adjuvant therapy for estrogen receptor (ER)-positive breast cancer (BC). However, many patients develop tamoxifen resistance, which results in recurrence and poor prognosis. Herein, we show that fatty acid oxidation (FAO) was activated in tamoxifen-resistant (TamR) ER-positive BC cells by performing bioinformatic and functional studies. We also reveal that CPT1A, the rate-limiting enzyme of FAO, was significantly overexpressed and that its enzymatic activity was enhanced in TamR cells. Mechanistically, the transcription factor c-Jun was activated by JNK kinase-mediated phosphorylation. Activated c-Jun bound to the TRE motif in the CPT1A promoter to drive CPT1A transcription and recruited CBP/P300 to chromatin, catalysing histone H3K27 acetylation to increase chromatin accessibility, which ensured more effective transcription of CPT1A and an increase in the FAO rate, eliminating the cytotoxic effects of tamoxifen in ER-positive BC cells. Pharmacologically, inhibiting CPT1A enzymatic activity with the CPT1 inhibitor etomoxir or blocking c-Jun phosphorylation with a JNK inhibitor restored the tamoxifen sensitivity of TamR cells. Clinically, high levels of phosphorylated c-Jun and CPT1A were observed in ER-positive BC tissues in patients with recurrence after tamoxifen therapy and were associated with poor survival. These results indicate that the assessment and targeting of the JNK/c-Jun-CPT1A-FAO axis will provide promising insights for clinical management, increased tamoxifen responses and improved outcomes for ER-positive BC patients.
... A separate in vivo study using a lung adenocarcinoma xenograft model demonstrated the anti-tumor effects of combining TVB-3664 with a KRAS inhibitor [252]. The In vivo Glioblastoma Temozolomide [322] In vivo HCC Antiangiogenic drug [287] In vivo Gastric cancer 5-fluorouracil [285] In vivo Nasopharyngeal carcinoma Radiotherapy [286] In vitro Breast cancer Radiotherapy [323] Perhexiline In vivo Colorectal and gastric cancer ...
Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.
