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CPT1A mRNA and protein levels are higher in metastatic tumor sites than in primary tumor sites. a CPT1A mRNA levels were higher in hepatic metastases of CRC patients than in primary tumors. n = 26, P = 0.0011. b Protein was harvested from six randomly selected tissue samples from (a). The protein levels of CPT1A were higher in hepatic metastases of CRC patients than primary tumors. c and d The expression of CPT1A was analyzed using IHC in a panel of phase III (198 primary tumors and 148 lymphatic metastases) and phase IV CRC tissues (90 primary tumors and 83 hepatic metastases). The staining was evaluated by two observers who were blinded to the patients’ information. P-values are noted in the figure, Student’s t-test, Chi-square test
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Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rat...
Citations
... Numerous studies have shown that Anoikis plays a significant role in the occurrence and development of cancer. CPT1A promotes colorectal cancer cell metastasis by inhibiting Anoikis [7]. In addition, the CamKK2-AMPK signaling pathway leads to the metastasis and invasion of LKB1-deficient lung cancer [8]. ...
Background
Osteosarcoma (OS) is the most common bone malignant tumor in children, and its prognosis is often poor. Anoikis is a unique mode of cell death.However, the effects of Anoikis in OS remain unexplored.
Method
Differential analysis of Anoikis-related genes was performed based on the metastatic and non-metastatic groups. Then LASSO logistic regression and SVM-RFE algorithms were applied to screen out the characteristic genes. Later, Univariate and multivariate Cox regression was conducted to identify prognostic genes and further develop the Anoikis-based risk score. In addition, correlation analysis was performed to analyze the relationship between tumor microenvironment, drug sensitivity, and prognostic models.
Results
We established novel Anoikis-related subgroups and developed a prognostic model based on three Anoikis-related genes (MAPK1, MYC, and EDIL3). The survival and ROC analysis results showed that the prognostic model was reliable. Besides, the results of single-cell sequencing analysis suggested that the three prognostic genes were closely related to immune cell infiltration. Subsequently, aberrant expression of two prognostic genes was identified in osteosarcoma cells. Nilotinib can promote the apoptosis of osteosarcoma cells and down-regulate the expression of MAPK1.
Conclusions
We developed a novel Anoikis-related risk score model, which can assist clinicians in evaluating the prognosis of osteosarcoma patients in clinical practice. Analysis of the tumor immune microenvironment and chemotherapeutic drug sensitivity can provide necessary insights into subsequent mechanisms. MAPK1 may be a valuable therapeutic target for neoadjuvant chemotherapy in osteosarcoma.
... CPT1A on the outer mitochondrial membrane is the rate-limiting enzyme of beta-oxidation, regulating the entrance of FA into the mitochondria. CPT1A is highly expressed in CRC cells, enhances FAO, and promotes the survival and distant metastasis of CRC cells [40]. In our study, the 10 FAs shared in different stages of CRC were mainly involved in linoleic acid metabolism and carnitine metabolism Wang (Table S7) (see Additional file 1). ...
Background
Understanding the metabolic changes in colorectal cancer (CRC) and exploring potential diagnostic biomarkers is crucial for elucidating its pathogenesis and reducing mortality. Cancer cells are typically derived from cancer tissues and can be easily obtained and cultured. Systematic studies on CRC cells at different stages are still lacking. Additionally, there is a need to validate our previous findings from human serum.
Methods
Ultrahigh-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS)-based metabolomics and lipidomics were employed to comprehensively measure metabolites and lipids in CRC cells at four different stages and serum samples from normal control (NR) and CRC subjects. Univariate and multivariate statistical analyses were applied to select the differential metabolites and lipids between groups. Biomarkers with good diagnostic efficacy for CRC that existed in both cells and serum were screened by the receiver operating characteristic curve (ROC) analysis. Furthermore, potential biomarkers were validated using metabolite standards.
Results
Metabolite and lipid profiles differed significantly among CRC cells at stages A, B, C, and D. Dysregulation of glycerophospholipid (GPL), fatty acid (FA), and amino acid (AA) metabolism played a crucial role in the CRC progression, particularly GPL metabolism dominated by phosphatidylcholine (PC). A total of 46 differential metabolites and 29 differential lipids common to the four stages of CRC cells were discovered. Eight metabolites showed the same trends in CRC cells and serum from CRC patients compared to the control groups. Among them, palmitoylcarnitine and sphingosine could serve as potential biomarkers with the values of area under the curve (AUC) more than 0.80 in the serum and cells. Their panel exhibited excellent performance in discriminating CRC cells at different stages from normal cells (AUC = 1.00).
Conclusions
To our knowledge, this is the first research to attempt to validate the results of metabolism studies of serum from CRC patients using cell models. The metabolic disorders of PC, FA, and AA were closely related to the tumorigenesis of CRC, with PC being the more critical factor. The panel composed of palmitoylcarnitine and sphingosine may act as a potential biomarker for the diagnosis of CRC, aiding in its prevention.
... Next, we tested whether cilnidipine prevents metabolic dysfunction caused by longtime PA exposure using FAO assay ( Figure 7A) [18]. Exposure to excess fatty acid is reported to cause reduction of mitochondrial function in cells [19]. ...
... Next, we tested whether cilnidipine prevents metabolic dysfunction caused by long-time PA exposure using FAO assay ( Figure 7A) [18]. Exposure to excess fatty acid is reported to cause reduction of mitochondrial function in cells [19]. ...
Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein–protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1–filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1–filamin interaction become a new strategy for the prevention or treatment of fatty liver disease.
... 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. ...
... Similarly, CPT1A expression level was elevated in colorectal cancer, particularly within metastatic sites. In-depth investigations have revealed that CPT1A-mediated fatty acid oxidation activation enabled colorectal cancer cells to resist anoikis [25]. Consistent with these findings, CPT1A was found to be upregulated in cervical cancer in this study, and its overexpression promoted the migration and proliferation of cervical cancer cells in vitro. ...
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.
... Elk-1 interaction partners found specifically in Aur/Plk phosphoproteome ( Figure 5(b), green color) include its transcriptional partner, SRF, known to coordinate actin cytoskel-eton and contribute to mitotic spindle orientation and asymmetric cell division [30][31][32]. In addition, other Elk-1interacting proteins include CPT1A, carnitine O-palmitoyltransferase, a mitochondrial membrane enzyme and plays a role in fatty acid oxidation, which is known to promoter metastasis and proliferation in cancer cells [33]; HM13, which catalyzes proteolysis of signal peptides in the ER and was found to contribute to tumor progression [34,35]; and choline/ethanolamine phosphotransferase CEPT1, which is involved in the synthesis of choline-containing phospholipids, which is reported to be upregulated in certain types of cancer [36]. ...
Elk-1 is a member of the ETS domain transcription factor superfamily that is phosphorylated upon mitogen-activated protein kinase (MAPK) pathway activation, which in turn regulated its interaction with partner protein serum response factor (SRF), leading to formation of a ternary complex with DNA. It has previously been reported that Elk-1 interacts with a mitotic kinase Aurora-A, although the mechanisms or the relevance of this interaction was unclear. Elk-1 was also reported to be phosphorylated by CDK5 on Thr417 residue. In this study, we show for the first time that this transcription factor interacts not only with Aurora-A but also with other mitotic kinases Aurora-B, Plk1, and Cdk1, and we define the interaction domain on Elk-1 to the first N-terminal 205 amino acids. We also describe putative phosphorylation sites of these mitotic kinases on Elk-1 and show that Elk-1 peptides containing these residues get phosphorylated by the mitotic kinases in in vitro kinase assays. We also perform bioinformatic analysis of mitotic phosphoproteomes and determine potential interaction partners for Elk-1 in Plk or Aurora phosphoproteomes. We propose that understanding the dynamic phosphorylation of Elk-1 by mitotic kinases is important and that it can present a novel target for anticancer strategies.
... Western blot analysis on adenoma tissues confirmed that downregulation of FASN leads to a decrease in GFPT1 and OGT protein expression, with a more profound effect on expression of GFPT1 ( Figure 1D). Interestingly, downregulation of FASN also leads to decreased expression of hexokinase 1 (HK1) in mice with homozygous deletion of Fasn and hexokinase (HK2) in mice with both hetero-and homozygous deletion of Fasn, but does not affect the levels of expression of pyruvate kinase isozymes M1/M2 (PKM1/2), which catalyzes the final reaction of glycolysis to produce pyruvate and ATP [38], and carnitine palmitoyltransferase I (CPT1), the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane [39]. Moreover, downregulation of OGT was associated with upregulation of O-GlcNAcase (OGA), an enzyme which, in contrast to OGT, removes the O-GlcNAc modification from the proteins [40] ( Figure 1D). ...
Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro-oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine–fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro and in vivo. Consistently, expression of FASN significantly correlates with expression of GFPT1 and OGT in human CRC tissues. shRNA-mediated downregulation of GFPT1 and OGT inhibits cellular proliferation and the level of protein O-GlcNAcylation in vitro, and knockdown of GFPT1 leads to a significant decrease in tumor growth and metastasis in vivo. Pharmacological inhibition of GFPT1 and OGT leads to significant inhibition of cellular proliferation and colony formation in CRC cells. In summary, our results show that overexpression of FASN increases the expression of GFPT1 and OGT as well as the level of protein O-GlcNAcylation to promote progression of CRC; targeting the hexosamine biosynthesis pathway could be a therapeutic approach for this disease.
... Next, we tested whether cilnidipine prevents metabolic dysfunction caused by long-time PA exposure using FAO assay ( Figure 7A) [18]. Exposure to excess fatty acid is reported to cause reduction of mitochondrial function in cells [19]. ...
Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, has potency to prevent pathological mitochondrial fission by inhibiting protein-protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel blocking action of cilnidipine, prevent the palmitic ac-id-induced Drp1-filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high fat diet-fed mouse livers. These results propose that targeting Drp1-filimin interaction becomes a new strategy for the prevention or treatment of fatty liver disease.
... 15,32,33 Studies have indicated a significant upregulation of CPT1A expression in breast cancer or leukemia, 16,34 where it could promote tumor progression and metastasis by inhibiting apoptosis or anoikis. 31,35 In contrast, our results revealed that CPT1A-mediated FAO was a crucial metabolic characteristic of LCSCs, and the suppression of CPT1A promoted ferroptosis sensitivity but not apoptosis in LCSCs. This heterogeneous mechanism of CPT1A promoting tumor cell survival suggests that targeting CPT1A to induce ferroptosis in LCSCs may be an effective strategy for NSCLC therapy. ...
Despite the successful application of immune checkpoint therapy, no response or recurrence is typical in lung cancer. Cancer stem cells (CSCs) have been identified as a crucial player in immunotherapy-related resistance. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with immunotherapy. Metabolic adaption of CSCs drives tumor resistance, yet the mechanisms of their ferroptosis defense in tumor immune evasion remain elusive. Here, through metabolomics, transcriptomics, a lung epithelial-specific Cpt1a -knockout mouse model, and clinical analysis, we demonstrate that CPT1A, a key rate-limiting enzyme of fatty acid oxidation, acts with L-carnitine, derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8 ⁺ T cells inactivation in lung cancer. Mechanistically, CPT1A restrains ubiquitination and degradation of c-Myc, while c-Myc transcriptionally activates CPT1A expression. The CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating, thereby suppressing ferroptosis in CSCs. Significantly, targeting CPT1A enhances immune checkpoint blockade-induced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice. The results illustrate the potential of a mechanism-guided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CSCs to improve the efficacy of lung cancer immunotherapy.
... These soluble factors contribute to maintaining cell viability, ultimately resulting in CTC resistance to HSS. Similarly, the membrane damage triggered by HSS ovarian cancer (HGSOC) [78][79][80]. Under detached culture conditions, CPT1A expression is induced by upregulation of the transcription factor ETV4 and downregulation of the ubiquitin enzyme RNF2 [78]. ...
... This coordinated mechanism leads to increased CPT1A expression at both the mRNA and protein levels. The induction of CPT1A maintains redox homeostasis by supplying reduced glutathione (GSH) for ROS elimination [78,79] and sustains mitochondrial respiration by utilizing monounsaturated fatty acids (MUFAs) [80], thereby contributing to cancer cell protection against anoikis. Notably, the Warburg effect contributes to anoikis resistance in cancer cells by attenuating the excessive production of ROS, which are byproducts of oxidative metabolism. ...
... Simultaneously, TPNVs disrupt the CD155/TIGIT pathway to restore the activity of CD8 + T cells. This strategy presents a promising avenue inhibitors such as etomoxir and perhexiline or via knockdown promotes anoikis and reduces CTC viability, subsequently inhibiting tumor growth and metastasis in vivo [78][79][80]. ...
Metastasis remains the principal trigger for relapse and mortality across diverse cancer types. Circulating tumor cells (CTCs), which originate from the primary tumor or its metastatic sites, traverse the vascular system, serving as precursors in cancer recurrence and metastasis. Nevertheless, before CTCs can establish themselves in the distant parenchyma, they must overcome significant challenges present within the circulatory system, including hydrodynamic shear stress (HSS), oxidative damage, anoikis, and immune surveillance. Recently, there has been a growing body of compelling evidence suggesting that a specific subset of CTCs can persist within the bloodstream, but the precise mechanisms of their survival remain largely elusive. This review aims to present an outline of the survival challenges encountered by CTCs and to summarize the recent advancements in understanding the underlying survival mechanisms, suggesting their implications for cancer treatment.
... Anoikis, a term derived from the Greek word for "homelessness," encapsulates a distinct form of apoptotic cell death arising from inadequate or improper cell adhesion [1]. At its core, Anoikis is a fundamental apoptotic process that plays a crucial role in the initiation and advancement of various malignancies [2][3][4]. This phenomenon is primarily instigated by the interplay of two apoptotic mechanisms: malfunctioning mitochondria or the activation of death receptors on the cell surface [5][6][7]. ...
... Consequently, this process has garnered significant attention in cancer research, providing insights into the intricate interplay between cell adhesion, apoptosis, and the progression of malignant tumors. As our understanding of Anoikis deepens, it unveils promising avenues for targeted therapeutic interventions aimed at disrupting this pivotal process in cancer development and metastatic dissemination [3,7,8]. ...
... Numerous investigations have shown that the CPT1A imbalance in colorectal cancer is directly associated with Anoikis resistance and ultimately results in a number of unfavorable outcomes, including cancer metastasis [3]. Furthermore, there is evidence that highlights the important contribution of CircCEMIP in prostate cancer cells. ...
