Aerobic exercise-induced HIF-1α upregulation in heart failure: exploring potential impacts on MCT1 and MPC1 regulation.

BACKGROUND: The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The hypoxic failing heart triggers hypoxia-inducible factor-1α (HIF-1α) actions in the cells sensitized to hypoxia and induces metabolic adaptation by accumulating HIF-1α. Furthermore, soluble monocarboxylic acid transporter protein 1 (MCT1) and mitochondrial pyruvate carrier 1 (MPC1), as key nodes of metabolic adaptation, affect metabolic homeostasis in the failing rat heart. Aerobic exercise training has been reported to retard the progression of HF due to enhancing HIF-1α levels as well as MCT1 expressions, whereas the effects of exercise on MCT1 and MPC1 in HF (hypoxia) remain elusive. This research aimed to investigate the action of exercise associated with MCT1 and MPC1 on HF under hypoxia. METHODS: The experimental rat models are composed of four study groups: sham stented (SHAM), HF sedentary (HF), HF short-term exercise trained (HF-E1), HF long-term exercise trained (HF-E2). HF was initiated via left anterior descending coronary artery ligation, the effects of exercise on the progression of HF were analyzed by ventricular ultrasound (ejection fraction, fractional shortening) and histological staining. The regulatory effects of HIF-1α on cell growth, MCT1 and MPC1 protein expression in hypoxic H9c2 cells were evaluated by HIF-1α activatort/inhibitor treatment and plasmid transfection. RESULTS: Our results indicate the presence of severe pathological remodelling (as evidenced by deep myocardial fibrosis, increased infarct size and abnormal hypertrophy of the myocardium, etc.) and reduced cardiac function in the failing hearts of rats in the HF group compared to the SHAM group. Treadmill exercise training ameliorated myocardial infarction (MI)-induced cardiac pathological remodelling and enhanced cardiac function in HF exercise group rats, and significantly increased the expression of HIF-1α (p < 0.05), MCT1 (p < 0.01) and MPC1 (p < 0.05) proteins compared to HF group rats. Moreover, pharmacological inhibition of HIF-1α in hypoxic H9c2 cells dramatically downregulated MCT1 and MPC1 protein expression. This phenomenon is consistent with knockdown of HIF-1α at the gene level. CONCLUSION: The findings propose that long-term aerobic exercise training, as a non- pharmacological treatment, is efficient enough to debilitate the disease process, improve the pathological phenotype, and reinstate cardiac function in HF rats. This benefit is most likely due to activation of myocardial HIF-1α and upregulation of MCT1 and MPC1.

Exploring MPC1 as a potential ferroptosis-linked biomarker in the cervical cancer tumor microenvironment: a comprehensive analysis.

BACKGROUND: The increasing problems of drug and radiotherapy resistance in cervical cancer underscores the need for novel methods for its management. Reports indicate that the expression of MPC1 may be associated with the tumor microenvironment and the occurrence of ferroptosis in cervical cancer. The objective of this study was to visually illustrate the prognostic significance and immunological characterization of MPC1 in cervical cancer. METHODS: The expression profile and prognostic significance of MPC1 were analyzed using various databases, including UALCAN, TIMER2, GEPIA2, and Kaplan-Meier Plotter. TISIDB, TIMER2, and immunohistochemical analysis were used to investigate the correlation between MPC1 expression and immune infiltration. GO enrichment analysis, KEGG analysis, Reactome analysis, ConsensusPathDB, and GeneMANIA were used to visualize the functional enrichment of MPC1 and signaling pathways related to MPC1. The correlation analysis was carried out to examine the relationship between MPC1 and Ferroptosis gene in TIMER 2.0, ncFO, GEPIA Database and Kaplan-Meier Plotter. RESULTS: We demonstrated that the expression levels of MPC1 in cervical cancer tissues were lower than those in normal cervical tissues. Kaplan-Meier survival curves showed shorter overall survival in cervical cancer patients with low levels of MPC1 expression. The expression of MPC1 was related to the infiltrating levels of tumor-infiltrating immune cells in cervical cancer. Moreover, MPC1 expression was associated with the iron-mediated cell death pathway, and several important ferroptosis genes were upregulated in cervical cancer cells. Furthermore, after knocking down MPC1 in HeLa cells, the expression of these genes decreased. CONCLUSION: These findings indicate that MPC1 functions as a prognostic indicator and plays a role in the regulation of the ferroptosis pathway in cervical cancer.

7-amino carboxycoumarin 2 inhibits lactate induced epithelial-to-mesenchymal transition via MPC1 in oral and breast cancer cells.

Lactate is an oncometabolite that play important role in tumor aggressiveness. Lactate from the tumor microenvironment (TME) is taken up by cancer cells as an energy resource via mitochondrial oxidative phosphorylation (or OXPHOS). In the present study, by using an online meta-analysis tool we demonstrated that in oral squamous cancer cells (OSCCs) glycolytic and OXPHOS governing genes are overexpressed, like in breast cancer. For experimental demonstration, we treated the OSCC cell line (SCC4) and breast cancer cells (MDA-MB-231) with sodium L-lactate and analyzed its effects on changes in EMT and migration. For the therapeutic intervention of lactate metabolism, we used AZD3965 (an MCT1 inhibitor), and 7ACC2 (an MPC inhibitor). Like breast cancer, oral cancer tissues showed increased transcripts of 12 genes that were previously shown to be associated with glycolysis and OXPHOS. We experimentally demonstrated that L-lactate treatment induced mesenchymal markers and migration of cancer cells, which was significantly neutralized by MPC inhibitor that is, 7ACC2. Such an effect on EMT status was not observed with AZD3965. Furthermore, we showed that lactate treatment increases the MPC1 expression in both cancer cells, and this might be the reason why cancer cells in the high lactate environment are more sensitive to 7ACC2. Overall, our present findings demonstrate that extracellular lactate positively regulates the MPC1 protein expression in cancer cells, thereby putting forward the notion of using 7ACC2 as a potential therapeutic alternative to inhibit malignant oxidative cancers. Future preclinical studies are warranted to validate the present findings.

Molecular mechanism of circHIPK3 in mitochondrial function in septic acute kidney injury.

Cell senescence, glycolysis, and mitochondrial deficit jointly regulate the development of septic acute kidney injury (SAKI). This study aimed to explore the role of circular RNA HIPK3 (circHIPK3) in mitochondrial function in SAKI. The SAKI mouse model was established by Candida albicans infection, followed by Western blot assay, measurements of serum lactate, and adenosine triphosphate (ATP), 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1) staining and flow cytometry. Human renal tubular epithelial cells were treated with lipopolysaccharide to establish the SAKI cell model, followed by cell counting kit-8 assay, tests of hexokinase activity, lactate production, oxygen consumption rate, extracellular acidification rate, ATP, and JC-1 staining, and Western blot assay. The roles of mitochondrial pyruvate carrier 1 (MPC1) were validated by kidney function tests, hematoxylin and eosin staining, periodic acid-Schiff staining, and SA-ß-gal staining. circHIPK3 downregulation reduced glycolysis and mitochondrial dysfunction both in vivo and in vitro through the microRNA (miR)-148b-3p/DNMT1/3a/Klotho axis. Inhibition of miR-148b-3p or Klotho increased glycolysis and mitochondrial dysfunction. Knockdown of MPC1 increased lactate content and decreased ATP levels and MMP both in vivo and in vitro. Collectively, circHIPK3, in concert with the miR-148b-3p/DNMT1/3a/Klotho axis, increased glycolysis, and inhibited the negative regulation of lactate production by MPC1, and aggravated mitochondrial dysfunction and cell senescence in SAKI.

Identification and characterization of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency.

Pyruvate, the end product of glycolysis, is a key metabolic molecule enabling mitochondrial adenosine triphosphate synthesis and takes part in multiple biosynthetic pathways within mitochondria. The mitochondrial pyruvate carrier (MPC) plays a vital role in transporting pyruvate from the cytosol into the organelle. In humans, MPC is a hetero-oligomeric complex formed by the MPC1 and MPC2 paralogs that are both necessary to stabilize each other and form a functional MPC. MPC deficiency (OMIM#614741) due to pathogenic MPC1 variants is a rare autosomal recessive disease involving developmental delay, microcephaly, growth failure, and increased serum lactate and pyruvate. To date, two MPC1 variants in four cases have been reported, though only one with a detailed clinical description. Herein, we report three novel pathogenic MPC1 variants in six patients from three unrelated families, identified within European, Kuwaiti, and Chinese mitochondrial disease patient cohorts, one of whom presented as a Leigh-like syndrome. Functional analysis in primary fibroblasts from the patients revealed decreased expression of MPC1 and MPC2. We rescued pyruvate-driven oxygen consumption rate in patient's fibroblasts by reconstituting with wild-type MPC1. Complementing homozygous MPC1 mutant cDNA with CRISPR-deleted MPC1 C2C12 cells verified the mechanism of variants: unstable MPC complex or ablated pyruvate uptake activity. Furthermore, we showed that glutamine and beta-hydroxybutyrate were alternative substrates to maintain mitochondrial respiration when cells lack pyruvate. In conclusion, we expand the clinical phenotypes and genotypes associated with MPC deficiency, with our studies revealing glutamine as a potential therapy for MPC deficiency.

Mitochondrial pyruvate carrier 1: a novel prognostic biomarker that predicts favourable patient survival in cancer.

Mitochondrial pyruvate carrier 1 (MPC1) is a key metabolic protein that regulates the transport of pyruvate into the mitochondrial inner membrane. MPC1 deficiency may cause metabolic reprogramming. However, whether and how MPC1 controls mitochondrial oxidative capacity in cancer are still relatively unknown. MPC1 deficiency was recently found to be strongly associated with various diseases and cancer hallmarks. We utilized online databases and uncovered that MPC1 expression is lower in many cancer tissues than in adjacent normal tissues. In addition, MPC1 expression was found to be substantially altered in five cancer types: breast-invasive carcinoma (BRCA), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and prostate adenocarcinoma (PRAD). However, in KIRC, LUAD, PAAD, and PRAD, high MPC1 expression is closely associated with favourable prognosis. Low MPC1 expression in BRCA is significantly associated with shorter overall survival time. MPC1 expression shows strong positive and negative correlations with immune cell infiltration in thymoma (THYM) and thyroid carcinoma (THCA). Furthermore, we have comprehensively summarized the current literature regarding the metabolic reprogramming effects of MPC1 in various cancers. As shown in the literature, MPC1 expression is significantly decreased in cancer tissue and associated with poor prognosis. We discuss the potential metabolism-altering effects of MPC1 in cancer, including decreased pyruvate transport ability; impaired pyruvate-driven oxidative phosphorylation (OXPHOS); and increased lactate production, glucose consumption, and glycolytic capacity, and the underlying mechanisms. These activities facilitate tumour progression, migration, and invasion. MPC1 is a novel cancer biomarker and potentially powerful therapeutic target for cancer diagnosis and treatment. Further studies aimed at slowing cancer progression are in progress.

MPC1 deletion is associated with poor prognosis and temozolomide resistance in glioblastoma.

OBJECT: Mitochondrial pyruvate carrier (MPC) proteins MPC1 and MPC2 form a transporter complex to control rate-limiting pyruvate transportation through the inner mitochondrial membrane. MPC1 plays a crucial role in the tumor metabolite and biosynthesis process. However, the role of MPC1 in glioblastoma (GBM) is unknown. METHODS: The Cancer Genome Atlas (TCGA) data set, which included 631 cases of GBM with genomic and clinical data, was obtained from the UCSC Xena browser. The clinical data set contained demographic, survival rate, and histological and pathological information. The association between MPC1 gene copy number segments and GBM patient overall survival was analyzed by Kaplan-Meier survival analysis, which was performed using the R2 web-based platform to identify the best cut-off. GraphPad Prism 7 was used to compare the differences in MPC1 gene copy number segments between various groups and subtypes. RESULTS: A total of 631 patients with glioblastoma (mean age 57.78 ± 14.36 years, 59% of males) were examined in this study, including 438 cases with MPC1 intact (MPC1 copy number segments > - 0.1, 69.4%) and 157 cases with MPC1 deletion (24.9%) tumors. Among the four GBM subtypes, the proneural group had the highest MPC1 copy number segments and GBM patients diagnosed with proneural subtype showed the best outcome. The expression of MPC1 transcripts was different in the TCGA-GBM dataset compared with the GTEx dataset. MPC1 copy number segments showed a significant correlation with MGMT copy number segments (r = 0.1322, p = 0.0012). MGMT gene expression level in MPC1 intact tumors was significantly lower than that in MPC1 deletion tumors (p = 0.0003). Significant relevancy was observed between better OS and the MPC1 intact group compared with the MPC1 deletion group (p = 0.020). Moreover, patients with MPC1 deletion tumors treated with temozolomide (TMZ) had worse survival than patients with MPC1 intact tumors (p = 0.027). CONCLUSIONS: Our results suggest a role of decreased MPC1 copy number segments in reducing overall survival in glioblastoma. MPC1 deletion is associated with poor response to TMZ chemotherapy in GBM.

Monocyte chemoattractant protein-1 as a marker of systemic lupus erythematosus: an observational study.

There is a pivotal need for new markers to be tested in every day clinical practice for systemic lupus erythematosus (SLE) and lupus nephritis (LN). The levels of monocyte chemoattractant protein-1 (MCP-1) in the serum and urine of 72 SLE patients (27 with LN and 45 without LN involvement) and 30 healthy individuals were studied to establish their clinical significance. The SLE Disease Activity Index (SLEDAI) was used to establish the disease activity. Urine and serum MCP-1 was determined using the sandwich enzyme immunosorbent assay. Urinary, but not serum MCP-1, positively correlated with proteinuria (r = 0.839; p < 0.001) and negatively correlated with glomerular filtration, evaluated using the modification of diet in renal disease (MDRD) formula (r = - 0.293; p < 0.05), and with C3 complement component in active LN patients (r = - 0.519, p = 0.019). Both serum and urinary MCP-1 demonstrated a positive correlation with SLEDAI (r = 0.318; p < 0.01 and r = 0.431; p < 0.001). We also demonstrated that the levels of serum and urinary MCP-1 were significantly higher in patients with SLE compared to healthy controls, regardless of the disease activity and renal involvement. We recommend MCP-1 measurement in the routine laboratory follow-up of the SLE patients.

MPC1-like Is a Placental Mammal-specific Mitochondrial Pyruvate Carrier Subunit Expressed in Postmeiotic Male Germ Cells.

Selective transport of pyruvate across the inner mitochondrial membrane by the mitochondrial pyruvate carrier (MPC) is a fundamental step that couples cytosolic and mitochondrial metabolism. The recent molecular identification of the MPC complex has revealed two interacting subunits, MPC1 and MPC2. Although in yeast, an additional subunit, MPC3, can functionally replace MPC2, no alternative MPC subunits have been described in higher eukaryotes. Here, we report for the first time the existence of a novel MPC subunit termed MPC1-like (MPC1L), which is present uniquely in placental mammals. MPC1L shares high sequence, structural, and topological homology with MPC1. In addition, we provide several lines of evidence to show that MPC1L is functionally equivalent to MPC1: 1) when co-expressed with MPC2, it rescues pyruvate import in a MPC-deleted yeast strain; 2) in mammalian cells, it can associate with MPC2 to form a functional carrier as assessed by bioluminescence resonance energy transfer; 3) in MPC1 depleted mouse embryonic fibroblasts, MPC1L rescues the loss of pyruvate-driven respiration and stabilizes MPC2 expression; and 4) MPC1- and MPC1L-mediated pyruvate imports show similar efficiency. However, we show that MPC1L has a highly specific expression pattern and is localized almost exclusively in testis and more specifically in postmeiotic spermatids and sperm cells. This is in marked contrast to MPC1/MPC2, which are ubiquitously expressed throughout the organism. To date, the biological importance of this alternative MPC complex during spermatogenesis in placental mammals remains unknown. Nevertheless, these findings open up new avenues for investigating the structure-function relationship within the MPC complex.

Mitochondrial pyruvate carrier 1 mediates abscisic acid-regulated stomatal closure and the drought response by affecting cellular pyruvate content in Arabidopsis thaliana.

BACKGROUND: Stomata are micropores surrounded by pairs of guard cells, and their opening is finely controlled to balance water vapor loss as transpiration and CO2 absorption for photosynthesis. The regulatory signaling network for stomatal movement is complicated, and increasing numbers of new genes have been shown to be involved in this process. Our previous study indicated that a member of the plant putative mitochondrial pyruvate carrier (MPC) family, NRGA1, is a negative regulator of guard cell abscisic acid (ABA) signaling. In this study, we identified novel physiological roles of pyruvate and MPC1, another member of the MPC family, in the regulation of stomatal closure in Arabidopsis. RESULTS: Loss-of-function mutants of MPC1 (mpc1) were hypersensitive to ABA-induced stomatal closure and ABA-activated guard cell slow-type anion currents, and showed a reduced rate of water loss upon drought treatment compared with wild-type plants. In contrast, plants overexpressing MPC1 showed a hyposensitive ABA response and increased sensitivity to drought stress. In addition, mpc1 mutants accumulated more pyruvate after drought or ABA treatment. The increased pyruvate content also induced stomatal closure and activated the slow-type anion channels of guard cells, and this process was dependent on the function of RbohD/F NADPH oxidases and reactive oxygen species concentrations in guard cells. CONCLUSIONS: Our findings revealed the essential roles of MPC1 and pyruvate in stomatal movement and plant drought resistance.

MPC1 and MPC2 expressions are associated with favorable clinical outcomes in prostate cancer.

BACKGROUND: Cancer cells exhibit an altered metabolism, which is characterized by a preference for aerobic glycolysis more than mitochondrial oxidation of pyruvate. Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) play a bottleneck role by transporting pyruvate into mitochondrial through the mitochondrial inner membrane. Therefore, their protein expression in cancers may be of clinical consequences. There are studies showing low levels of MPC1 expression in colon, kidney and lung cancers, and the expression of MPC1 correlates with poor prognosis. However, the expression status of MPC1 and MPC2 in prostate cancer (PCA) is unclear. METHODS: In this study, expression of MPC1 and MPC2 in LNCaP and DU145 prostate cancer cell lines was examined by immunocytochemistry (ICC) and Western blotting. Compared to the LNCaP cells, lower levels of MPC1 and MPC2 expression in the DU145 cell line was identified. We then extended our study to 88 patients with prostate cancer who underwent transurethral electro-vaporization of prostate or radical prostatectomy at the First Affiliated Hospital of Zhengzhou University, Henan, China. Patient-derived paraffin embedded PCA specimens were collected for immunohistochemistry (IHC). Correlations with clinicopathologic factors were evaluated by Chi-square or Fisher´s exact probability tests. Overall survival (OS) rates were determined using the Kaplan-Meier estimator. The Cox proportional hazard regression model was used in univariate analysis and multivariate analysis to identify factors significantly correlated with prognosis. RESULTS: Linear regression analysis revealed that MPC1 expression level was positively correlated with MPC2 expression (r = 0.375, P = 0.006) in the prostate cancers. MPC1 expression was negatively associated with UICC stage (P = 0.031). While UICC stage (P < 0.001) and lymph node metastasis (P = 0.002) were negatively associated with MPC2 expression. Positive MPC1 or MPC2 expression in cancer tissues was significantly associated with higher OS (P < 0.05). The multivariate analysis showed that both MPC1 and MPC2 expressions in PCA were independent prognostic factors for higher OS (For MPC1: RR = 0.654, 95% CI: 0.621-0690, P < 0.001; For MPC2: RR = 0.696, 95% CI: 0.660-0.734, P < 0.001). CONCLUSIONS: Our study indicates that MPC1 and MPC2 expressions are of prognostic values in PCAs and that positive expression of MPC1 or MPC2 is a predictor of favorable outcome.

Sirt3 binds to and deacetylates mitochondrial pyruvate carrier 1 to enhance its activity.

Mitochondrial pyruvate carrier (MPC), composed of MPC1 and MPC2, can modulate pyruvate oxidation in mitochondrial and MPC1 expression correlates with poor prognosis of multiple cancers. Here, we reported that MPC1 is acetylated and its main acetylation sites are: K45 and K46. Sirt3 binds to and deacetylates MPC1. High glucose decreases MPC1 acetylation level by increasing Sirt3-MPC1 binding. Furthermore, acetylation mimic mutation of MPC1 reduces it activity and abolishes its function in inhibition of colon cancer cell growth. These results reveal a novel post-translational regulation of MPC1 by Sirt3, which is important for its activity and colon cancer cell growth.

Pancreatic cancer tumor organoids exhibit subtype-specific differences in metabolic profiles.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease characterized by complex metabolic rewiring that enables growth in changing nutrient availability and oxygen conditions. Transcriptome-based prognostic PDAC tumor subtypes, known as 'basal-like' and 'classical' subtypes are associated with differences in metabolic gene expression including genes involved in glycolysis. Tumor subtype-specific metabolism phenotypes may provide new targets for treatment development in PDAC, but their functional relevance has not been fully elucidated. We aimed to investigate differences in metabolic profiles and transcriptomes in tumor models derived from patients with basal-like and classical tumors. METHODS: Patient-derived organoids (PDOs) were established from tumor biopsies collected from patients with metastatic PDAC, including three PDOs from basal-like and five PDOs from classical tumors. Metabolic analyses included assessment of differences in metabolic activity using Seahorse Glycolysis and Mito Stress tests and 13C-glucose metabolites tracing analysis. In order to investigate the influence of mitochondrial pyruvate transport on metabolic differences, PDOs were treated with the mitochondrial pyruvate carrier 1 (MPC1) inhibitor UK-5099. Prognostic relevance of MPC1 was determined using a tumor tissue microarray (TMA) in resectable, and proteomics profiling in metastatic PDAC datasets. Whole genome and transcriptome sequencing, differential gene expression and gene set enrichment analyses were performed in PDOs. RESULTS: Metastatic PDAC PDOs showed subtype-specific differences in glycolysis and oxidative phosphorylation (OXPHOS). Basal-like tumor-derived PDOs had a lower baseline extracellular acidification rate, but higher glycolytic reserves and oxygen consumption rate (OCR) than classical tumor-derived PDOs. OCR difference was eliminated following treatment with UK-5099. In the 13C-glucose metabolites tracing experiment, a basal-like tumor PDO showed lower fractions of some M + 2 metabolites but higher sensitivity to UK-5099 mediated reduction in M + 2 metabolites than a classical tumor PDO. Protein level analyses revealed lower MPC1 protein levels in basal-like PDAC cases and association of low MPC1 levels with clinicopathologic parameters of tumor aggressiveness in PDAC. PDO differential gene expression analyses identified additional subtype-specific cellular pathways and potential disease outcome biomarkers. CONCLUSIONS: Our findings point to distinct metabolic profiles in PDAC subtypes with basal-like tumor PDOs showing higher OXPHOS and sensitivity to MPC1 inhibition. Subtypes-specific metabolic vulnerabilities may be exploited for selective therapeutic targeting.

Mitochondrial Pyruvate Carrier 1 as a Novel Prognostic Biomarker in Non-Small Cell Lung Cancer.

BACKGROUND: Abnormal mitochondrial pyruvate carrier 1 (MPC1) expression plays a key role in tumor metabolic reprogramming and progression. Understanding its significance in non-small cell lung cancer (NSCLC) is crucial for identifying therapeutic targets. METHODS: TIMER 2.0 was utilized to assess the expression of MPC1 in both normal and cancer tissues in pan-cancer. Overall survival (OS) differences between high and low MPC1 expression were analyzed in NSCLC using the Cancer Genome Atlas (TCGA) datasets. We also examined the expression of MPC1 in NSCLC cell lines using western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addition, the tissue samples and clinical information of 80 patients with NSCLC from our hospital were collected. Immunohistochemistry (IHC) was used to assess MPC1 expression, and OS was evaluated using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic values of the clinical characteristics and MPC1expression. RESULTS: Analysis of public databases suggested that MPC1 was downregulated in NSCLC compared to that in normal lung tissue and predicted poor prognosis. In addition, the expression of MPC1 in NSCLC cell lines was lower than that in human bronchial epithelial (HBE) cells at both protein and mRNA levels. Further clinical analysis suggested that MPC1 expression was correlated with age, tumor T stage, and TNM stage. Kaplan-Meier analysis revealed that NSCLC patients with high MPC1 expression had a better prognosis, particularly in lung adenocarcinoma (LUAD), whereas no survival benefit was observed in lung squamous cell carcinoma (LUSC). Univariate and multivariate analyses suggested that MPC1 was an independent prognostic factor for patients with NSCLC. CONCLUSIONS: MPC1 is poorly expressed in NSCLC, particularly in LUAD, which predicts a poor prognosis and may serve as an independent prognostic factor. Further studies on MPC1 may reveal new targets for the treatment of NSCLC.

Prox1 Suppresses the Proliferation of Breast Cancer Cells via Direct Inhibition of c-Myc Gene Expression.

Breast cancer is one of the most lethal malignancies in women worldwide and is characterized by rapid growth and low survival rates, despite advances in tumor biology and therapies. Novel therapeutic approaches require new insights into the molecular mechanisms of malignant transformation and progression. To this end, here, we identified Prox1 as a negative regulator of proliferation and tumor-related metabolism in breast cancer. In particular, we showed that breast tumors from human patients exhibited reduced levels of Prox1 expression, while high expression levels of Prox1 were associated with a favorable prognosis in breast cancer patients. Moreover, we experimentally demonstrated that Prox1 was sufficient to strongly suppress proliferation, migration, and the Warburg effect in human breast cancer cells without inducing apoptosis. Most importantly, over-expression of Prox1 inhibited breast tumor growth in vivo in both heterotopic and orthotopic xenograft mouse models. The anti-tumorigenic effect of Prox1 was mediated by the direct repression of c-Myc transcription and its downstream target genes. Consistently, c-Myc over-expression from an artificial promoter that was not targeted by Prox1 reversed Prox1's anti-tumor effects. These findings suggest that Prox1 has a tumor suppressive role via direct transcriptional regulation of c-Myc, making it a promising therapeutic gene for breast cancer.

Mitochondrial pyruvate carrier 1 regulates ferroptosis in drug-tolerant persister head and neck cancer cells via epithelial-mesenchymal transition.

Cancer cells evolve to survive as 'persister cells' resistant to various chemotherapeutic agents. Persister cancer cells retain mesenchymal traits that are vulnerable to ferroptosis by iron-dependent accumulation of lethal lipid peroxidation. Regulation of the KDM5A-MPC1 axis might shift cancer cells to have mesenchymal traits via epithelial-mesenchymal transition process. Therefore, we examined the therapeutic potentiality of KDM5A-MPC1 axis regulation in promoting ferroptosis in erlotinib-tolerant persister head and neck cancer cells (erPCC). ErPCC acquired mesenchymal traits and disabled antioxidant program that were more vulnerable to ferroptosis inducers of RSL3, ML210, sulfasalazine, and erastin. GPX4 and xCT suppression caused increased sensitivity to ferroptosis in vivo models of GPX4 genetic silencing. KDM5A expression increased and MPC1 expression decreased in erPCC. KDM5A inhibition increased MPC1 expression and decreased sensitivity to ferroptosis inducers in erPCC. MPC1 suppression increased vulnerability to ferroptosis in vitro and in vivo by retaining mesenchymal traits and glutaminolysis. Low expression of MPC1 was associated with low overall survival from the TCGA data. Our data suggest that regulation of the KDM5A-MPC1 axis contributes to promoting cancer ferroptosis susceptibility.

The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.

PURPOSE: Re-examine the current metabolic models. METHODS: Review of literature and gene networks. RESULTS: Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.

Oil Body Formation in Marchantia polymorpha Is Controlled by MpC1HDZ and Serves as a Defense against Arthropod Herbivores.

The origin of a terrestrial flora in the Ordovician required adaptation to novel biotic and abiotic stressors. Oil bodies, a synapomorphy of liverworts, accumulate secondary metabolites, but their function and development are poorly understood. Oil bodies of Marchantia polymorpha develop within specialized cells as one single large organelle. Here, we show that a class I homeodomain leucine-zipper (C1HDZ) transcription factor controls the differentiation of oil body cells in two different ecotypes of the liverwort M. polymorpha, a model genetic system for early divergent land plants. In flowering plants, these transcription factors primarily modulate responses to abiotic stress, including drought. However, loss-of-function alleles of the single ortholog gene, MpC1HDZ, in M. polymorpha did not exhibit phenotypes associated with abiotic stress. Rather, Mpc1hdz mutant plants were more susceptible to herbivory, and total plant extracts of the mutant exhibited reduced antibacterial activity. Transcriptomic analysis of the mutant revealed a reduction in expression of genes related to secondary metabolism that was accompanied by a specific depletion of oil body terpenoid compounds. Through time-lapse imaging, we observed that MpC1HDZ expression maxima precede oil body formation, indicating that MpC1HDZ mediates differentiation of oil body cells. Our results indicate that M. polymorpha oil bodies, and MpC1HDZ, are critical for defense against herbivory, but not for abiotic stress tolerance. Thus, C1HDZ genes were co-opted to regulate separate responses to biotic and abiotic stressors in two distinct land plant lineages.

MPC-1 expression in myeloma cells is associated with the efficacy of bortezomib therapy.

The use of bortezomib in the clinic has significantly improved outcomes for patients with multiple myeloma (MM), even those harboring high-risk cytogenetic abnormalities or those classified in the high-risk category according to the International Staging System (ISS). In this study, we analyzed the association between immunophenotyping on myeloma cells and the clinical outcomes of patients who received bortezomib-based regimens as first-line therapy. Immunophenotypic analysis before bortezomib therapy was performed by flow cytometry, and whether the immunophenotyping results influenced the clinical outcomes of the patients was investigated. Seventy-four newly diagnosed patients with MM were included in this study. We found that the expression of MPC-1 significantly predicted the time to next therapy (TNT), with a longer TNT in the MPC-1 positive group (p = 0.005), whereas it did not affect overall survival (OS; p = 0.773). In addition, we found that CD45-positivity was associated with shorter TNT (p = 0.0432). Following ISS assessment at treatment initiation, patients who were classified as stage I showed a slightly longer OS compared to those at stage II or III; however, these results were not significant (p = 0.0987). Furthermore, multivariate analysis revealed the prognostic significance of MPC-1 expression, as MPC-1-negativity was associated with a worse TNT. The combination of MPC-1 and CD45 status more sensibly predicted the TNT for bortezomib therapy. Our results demonstrate the clinical importance of immunophenotyping on myeloma cells to determine patient prognoses in this era of novel therapeutic agents.

Inhibition of ERRα Prevents Mitochondrial Pyruvate Uptake Exposing NADPH-Generating Pathways as Targetable Vulnerabilities in Breast Cancer.

Most cancer cells exhibit metabolic flexibility, enabling them to withstand fluctuations in intratumoral concentrations of glucose (and other nutrients) and changes in oxygen availability. While these adaptive responses make it difficult to achieve clinically useful anti-tumor responses when targeting a single metabolic pathway, they can also serve as targetable metabolic vulnerabilities that can be therapeutically exploited. Previously, we demonstrated that inhibition of estrogen-related receptor alpha (ERRα) significantly disrupts mitochondrial metabolism and that this results in substantial antitumor activity in animal models of breast cancer. Here we show that ERRα inhibition interferes with pyruvate entry into mitochondria by inhibiting the expression of mitochondrial pyruvate carrier 1 (MPC1). This results in a dramatic increase in the reliance of cells on glutamine oxidation and the pentose phosphate pathway to maintain nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis. In this manner, ERRα inhibition increases the efficacy of glutaminase and glucose-6-phosphate dehydrogenase inhibitors, a finding that has clinical significance.