Cancer & Metabolism最新文献

{"title":"Metabolic changes preceding bladder cancer occurrence among Korean men: a nested case-control study from the KCPS-II cohort.","authors":"Youngmin Han, Unchong Kim, Keum Ji Jung, Ji-Young Lee, Kwangbae Lee, Sang Yop Shin, Heejin Kimm, Sun Ha Jee","doi":"10.1186/s40170-023-00324-0","DOIUrl":"10.1186/s40170-023-00324-0","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer (BLCA) research in Koreans is still lacking, especially in focusing on the prediction of BLCA. The current study aimed to discover metabolic signatures related to BLCA onset and confirm its potential as a biomarker.</p><p><strong>Methods: </strong>We designed two nested case-control studies using Korean Cancer Prevention Study (KCPS)-II. Only males aged 35-69 were randomly selected and divided into two sets by recruitment organizations [set 1, BLCA (n = 35) vs. control (n = 35); set 2, BLCA (n = 31) vs. control (n = 31)]. Baseline serum samples were analyzed by non-targeted metabolomics profiling, and OPLS-DA and network analysis were performed. Calculated genetic risk score (GRS) for BLCA from all KCPS participants was utilized for interpreting metabolomics data.</p><p><strong>Results: </strong>Critical metabolic signatures shown in the BLCA group were dysregulation of lysine metabolism and tryptophan-indole metabolism. Furthermore, the prediction model consisting of metabolites (lysine, tryptophan, indole, indoleacrylic acid, and indoleacetaldehyde) reflecting these metabolic signatures showed mighty BLCA predictive power (AUC: 0.959 [0.929-0.989]). The results of metabolic differences between GRS-high and GRS-low groups in BLCA indicated that the pathogenesis of BLCA is associated with a genetic predisposition. Besides, the predictive ability for BLCA on the model using GRS and five significant metabolites was powerful (AUC: 0.990 [0.980-1.000]).</p><p><strong>Conclusion: </strong>Metabolic signatures shown in the present research may be closely associated with BLCA pathogenesis. Metabolites involved in these could be predictive biomarkers for BLCA. It could be utilized for early diagnosis, prognostic diagnosis, and therapeutic targets for BLCA.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"23"},"PeriodicalIF":5.9,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138486722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autofluorescence imaging of endogenous metabolic cofactors in response to cytokine stimulation of classically activated macrophages.","authors":"Shelby N Bess, Matthew J Igoe, Abby C Denison, Timothy J Muldoon","doi":"10.1186/s40170-023-00325-z","DOIUrl":"10.1186/s40170-023-00325-z","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are one of the most prevalent subsets of immune cells within the tumor microenvironment and perform a range of functions depending on the cytokines and chemokines released by surrounding cells and tissues. Recent research has revealed that macrophages can exhibit a spectrum of phenotypes, making them highly plastic due to their ability to alter their physiology in response to environmental cues. Recent advances in examining heterogeneous macrophage populations include optical metabolic imaging, such as fluorescence lifetime imaging (FLIM), and multiphoton microscopy. However, the method of detection for these systems is reliant upon the coenzymes NAD(P)H and FAD, which can be affected by factors other than cytoplasmic metabolic changes. In this study, we seek to validate these optical measures of metabolism by comparing optical results to more standard methods of evaluating cellular metabolism, such as extracellular flux assays and the presence of metabolic intermediates.</p><p><strong>Methods: </strong>Here, we used autofluorescence imaging of endogenous metabolic co-factors via multiphoton microscopy and FLIM in conjunction with oxygen consumption rate and extracellular acidification rate through Seahorse extracellular flux assays to detect changes in cellular metabolism in quiescent and classically activated macrophages in response to cytokine stimulation.</p><p><strong>Results: </strong>Based on our Seahorse XFP flux analysis, M0 and M1 macrophages exhibit comparable trends in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Autofluorescence imaging of M0 and M1 macrophages was not only able to show acute changes in the optical redox ratio from pre-differentiation (0 hours) to 72 hours post-cytokine differentiation (M0: 0.320 to 0.258 and M1: 0.316 to 0.386), mean NADH lifetime (M0: 1.272 ns to 1.379 ns and M1: 1.265 ns to 1.206 ns), and A1/A2 ratio (M0: 3.452 to ~ 4 and M1: 3.537 to 4.529) but could also detect heterogeneity within each macrophage population.</p><p><strong>Conclusions: </strong>Overall, the findings of this study suggest that autofluorescence metabolic imaging could be a reliable technique for longitudinal tracking of immune cell metabolism during activation post-cytokine stimulation.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"22"},"PeriodicalIF":5.9,"publicationDate":"2023-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10644562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92152738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of chemotherapy on resting energy expenditure, body composition, and cancer-related fatigue in women with breast cancer: a prospective cohort study.","authors":"Timia Van Soom, Wiebren Tjalma, Konstantinos Papadimitriou, Nick Gebruers, Eric van Breda","doi":"10.1186/s40170-023-00322-2","DOIUrl":"10.1186/s40170-023-00322-2","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) is the most prevalent tumor in women. Improvements in treatment led to declined mortality, resulting in more survivors living with cancer- or therapy-induced comorbidities. In this study, we investigated the impact of neoplasia and chemotherapy on resting energy expenditure (REE) and body composition, in relation to cancer-related fatigue. Inflammatory parameters were checked as possible explanation for changes in REE.</p><p><strong>Methods: </strong>Fifty-six women participated: 20 women with BC and 36 healthy controls. Patients were assessed at baseline (T0) and follow-up (T1) after 12 weeks of chemotherapy. Controls were measured once. REE was assessed with indirect calorimetry: body composition (body weight, fat mass, fat-free mass) by air plethysmography. The multidimensional fatigue index (MFI-20) was used to analyze fatigue. Baseline measurements of patients were compared to results of the healthy controls with the independent-samples T-test. The paired-samples T-test investigated the effects of chemotherapy from T0 to T1. A Pearson correlation analysis was conducted between REE, body composition, and fatigue and between REE, body composition, and inflammatory parameters. A linear regression analysis was fitted to estimate the contribution of the significantly correlated parameters. The measured REE at T0 and T1 was compared to the predicted REE to analyze the clinical use of the latter.</p><p><strong>Results: </strong>At baseline, patients with BC had significantly higher REE in the absence of differences in body composition. From baseline to T1, REE and body weight did not change. In contrast, fat-free mass declined significantly with concordant increase in fat mass. Fatigue deteriorated significantly. C-reactive protein at baseline predicted the change in energy expenditure. Predicted REE significantly underestimated measured REE.</p><p><strong>Conclusions: </strong>Women with BC have higher REE in the tumor-bearing state compared to healthy controls. Chemotherapy does not affect REE but alters body composition. Predictive equations are invalid in the BC population. Results of our study can be used to implement personalized nutritional interventions to support energy expenditure and body composition and minimize long-term comorbidities.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"21"},"PeriodicalIF":5.9,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10636951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72013600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATM inhibition blocks glucose metabolism and amplifies the sensitivity of resistant lung cancer cell lines to oncogene driver inhibitors.","authors":"Cristina Terlizzi, Viviana De Rosa, Francesca Iommelli, Antonio Pezone, Giovanna G Altobelli, Maurizio Maddalena, Jelena Dimitrov, Caterina De Rosa, Carminia Maria Della Corte, Vittorio Enrico Avvedimento, Silvana Del Vecchio","doi":"10.1186/s40170-023-00320-4","DOIUrl":"10.1186/s40170-023-00320-4","url":null,"abstract":"<p><strong>Background: </strong>ATM is a multifunctional serine/threonine kinase that in addition to its well-established role in DNA repair mechanisms is involved in a number of signaling pathways including regulation of oxidative stress response and metabolic diversion of glucose through the pentose phosphate pathway. Oncogene-driven tumorigenesis often implies the metabolic switch from oxidative phosphorylation to glycolysis which provides metabolic intermediates to sustain cell proliferation. The aim of our study is to elucidate the role of ATM in the regulation of glucose metabolism in oncogene-driven cancer cells and to test whether ATM may be a suitable target for anticancer therapy.</p><p><strong>Methods: </strong>Two oncogene-driven NSCLC cell lines, namely H1975 and H1993 cells, were treated with ATM inhibitor, KU55933, alone or in combination with oncogene driver inhibitors, WZ4002 or crizotinib. Key glycolytic enzymes, mitochondrial complex subunits (OXPHOS), cyclin D1, and apoptotic markers were analyzed by Western blotting. Drug-induced toxicity was assessed by MTS assay using stand-alone or combined treatment with KU55933 and driver inhibitors. Glucose consumption, pyruvate, citrate, and succinate levels were also analyzed in response to KU55933 treatment. Both cell lines were transfected with ATM-targeted siRNA or non-targeting siRNA and then exposed to treatment with driver inhibitors.</p><p><strong>Results: </strong>ATM inhibition deregulates and inhibits glucose metabolism by reducing HKII, p-PKM2^Tyr105, p-PKM2^Ser37, E1α subunit of pyruvate dehydrogenase complex, and all subunits of mitochondrial complexes except ATP synthase. Accordingly, glucose uptake and pyruvate concentrations were reduced in response to ATM inhibition, whereas citrate and succinate levels were increased in both cell lines indicating the supply of alternative metabolic substrates. Silencing of ATM resulted in similar changes in glycolytic cascade and OXPHOS levels. Furthermore, the driver inhibitors amplified the effects of ATM downregulation on glucose metabolism, and the combined treatment with ATM inhibitors enhanced the cytotoxic effect of driver inhibitors alone by increasing the apoptotic response.</p><p><strong>Conclusions: </strong>Inhibition of ATM reduced both glycolytic enzymes and OXPHOS levels in oncogene-driven cancer cells and enhanced apoptosis induced by driver inhibitors thus highlighting the possibility to use ATM and the driver inhibitors in combined regimens of anticancer therapy in vivo.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"20"},"PeriodicalIF":5.9,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71478337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells.","authors":"Shyamananda Singh Mayengbam,&nbsp;Abhijeet Singh,&nbsp;Himanshi Yaduvanshi,&nbsp;Firoz Khan Bhati,&nbsp;Bhavana Deshmukh,&nbsp;Dipti Athavale,&nbsp;Pranay L Ramteke,&nbsp;Manoj Kumar Bhat","doi":"10.1186/s40170-023-00321-3","DOIUrl":"10.1186/s40170-023-00321-3","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"19"},"PeriodicalIF":5.9,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10604918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54227729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.","authors":"Amy K Holt, Arafath K Najumudeen, Tracey J Collard, Hao Li, Laura M Millett, Ashley J Hoskin, Danny N Legge, Eleanor M H Mortensson, Dustin J Flanagan, Nicholas Jones, Madhu Kollareddy, Penny Timms, Matthew D Hitchings, James Cronin, Owen J Sansom, Ann C Williams, Emma E Vincent","doi":"10.1186/s40170-023-00318-y","DOIUrl":"10.1186/s40170-023-00318-y","url":null,"abstract":"<p><strong>Background: </strong>To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.</p><p><strong>Methods: </strong>We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.</p><p><strong>Results: </strong>We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apc^fl/fl mice in vivo.</p><p><strong>Conclusions: </strong>Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"18"},"PeriodicalIF":5.9,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49674628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Untargeted plasma metabolomics and risk of colorectal cancer-an analysis nested within a large-scale prospective cohort.","authors":"Linda Vidman, Rui Zheng, Stina Bodén, Anton Ribbenstedt, Marc J Gunter, Richard Palmqvist, Sophia Harlid, Carl Brunius, Bethany Van Guelpen","doi":"10.1186/s40170-023-00319-x","DOIUrl":"10.1186/s40170-023-00319-x","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, but if discovered at an early stage, the survival rate is high. The aim of this study was to identify novel markers predictive of future CRC risk using untargeted metabolomics.</p><p><strong>Methods: </strong>This study included prospectively collected plasma samples from 902 CRC cases and 902 matched cancer-free control participants from the population-based Northern Sweden Health and Disease Study (NSHDS), which were obtained up to 26 years prior to CRC diagnosis. Using reverse-phase liquid chromatography-mass spectrometry (LC-MS), data comprising 5015 metabolic features were obtained. Conditional logistic regression was applied to identify potentially important metabolic features associated with CRC risk. In addition, we investigated if previously reported metabolite biomarkers of CRC risk could be validated in this study population.</p><p><strong>Results: </strong>In the univariable analysis, seven metabolic features were associated with CRC risk (using a false discovery rate cutoff of 0.25). Two of these could be annotated, one as pyroglutamic acid (odds ratio per one standard deviation increase = 0.79, 95% confidence interval, 0.70-0.89) and another as hydroxytigecycline (odds ratio per one standard deviation increase = 0.77, 95% confidence interval, 0.67-0.89). Associations with CRC risk were also found for six previously reported metabolic biomarkers of prevalent and/or incident CRC: sebacic acid (inverse association) and L-tryptophan, 3-hydroxybutyric acid, 9,12,13-TriHOME, valine, and 13-OxoODE (positive associations).</p><p><strong>Conclusions: </strong>These findings suggest that although the circulating metabolome may provide new etiological insights into the underlying causes of CRC development, its potential application for the identification of individuals at higher risk of developing CRC is limited.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"17"},"PeriodicalIF":5.9,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41232483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of predictive biomarkers for endometrial cancer diagnosis and treatment response monitoring using plasma metabolome profiling.","authors":"Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Yoshiko Shima, Bin Li, Ikuko N Motoike, Yusuke Shibuya, Tatsuya Hagihara, Shogo Shigeta, Hideki Tokunaga, Daisuke Saigusa, Kengo Kinoshita, Seizo Koshiba, Nobuo Yaegashi","doi":"10.1186/s40170-023-00317-z","DOIUrl":"10.1186/s40170-023-00317-z","url":null,"abstract":"<p><strong>Background: </strong>Endometrial cancer (EMC) is the most common female genital tract malignancy with an increasing prevalence in many countries including Japan, a fact that renders early detection and treatment necessary to protect health and fertility. Although early detection and treatment are necessary to further improve the prognosis of women with endometrial cancer, biomarkers that accurately reflect the pathophysiology of EMC patients are still unclear. Therefore, it is clinically critical to identify biomarkers to assess diagnosis and treatment efficacy to facilitate appropriate treatment and development of new therapies for EMC.</p><p><strong>Methods: </strong>In this study, wide-targeted plasma metabolome analysis was performed to identify biomarkers for EMC diagnosis and the prediction of treatment responses. The absolute quantification of 628 metabolites in plasma samples from 142 patients with EMC was performed using ultra-high-performance liquid chromatography with tandem mass spectrometry.</p><p><strong>Results: </strong>The concentrations of 111 metabolites increased significantly, while the concentrations of 148 metabolites decreased significantly in patients with EMC compared to healthy controls. Specifically, LysoPC and TGs, including unsaturated fatty acids, were reduced in patients with stage IA EMC compared to healthy controls, indicating that these metabolic profiles could be used as early diagnostic markers of EMC. In contrast, blood levels of amino acids such as histidine and tryptophan decreased as the risk of recurrence increased and the stages of EMC advanced. Furthermore, a marked increase in total TG and a decrease in specific TGs and free fatty acids including polyunsaturated fatty acids levels were observed in patients with EMC. These results suggest that the polyunsaturated fatty acids in patients with EMC are crucial for disease progression.</p><p><strong>Conclusions: </strong>Our data identified specific metabolite profiles that reflect the pathogenesis of EMC and showed that these metabolites correlate with the risk of recurrence and disease stage. Analysis of changes in plasma metabolite profiles could be applied for the early diagnosis and monitoring of the course of treatment of EMC patients.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"16"},"PeriodicalIF":5.9,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41192081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol reprograms glucose and lipid metabolism to promote proliferation in colon cancer cells.","authors":"Shyamananda Singh Mayengbam, Abhijeet Singh, Himanshi Yaduvanshi, Firoz Khan Bhati, Bhavana Deshmukh, Dipti Athavale, Pranay L Ramteke, Manoj Kumar Bhat","doi":"10.1186/s40170-023-00315-1","DOIUrl":"10.1186/s40170-023-00315-1","url":null,"abstract":"<p><p>Hypercholesterolemia is often correlated with obesity which is considered a risk factor for various cancers. With the growing population of hypercholesterolemic individuals, there is a need to understand the role of increased circulatory cholesterol or dietary cholesterol intake towards cancer etiology and pathology. Recently, abnormality in the blood cholesterol level of colon cancer patients has been reported. In the present study, we demonstrate that alteration in cholesterol levels (through a high-cholesterol or high-fat diet) increases the incidence of chemical carcinogen-induced colon polyp occurrence and tumor progression in mice. At the cellular level, low-density lipoprotein cholesterol (LDLc) and high-density lipoprotein cholesterol (HDLc) promote colon cancer cell proliferation by tuning the cellular glucose and lipid metabolism. Mechanistically, supplementation of LDLc or HDLc promotes cellular glucose uptake, and utilization, thereby, causing an increase in lactate production by colon cancer cells. Moreover, LDLc or HDLc upregulates aerobic glycolysis, causing an increase in total ATP production through glycolysis, and a decrease in ATP generation by OXPHOS. Interestingly, the shift in the metabolic status towards a more glycolytic phenotype upon the availability of cholesterol supports rapid cell proliferation. Additionally, an alteration in the expression of the molecules involved in cholesterol uptake along with the increase in lipid and cholesterol accumulation was observed in cells supplemented with LDLc or HDLc. These results indicate that colon cancer cells directly utilize the cholesterol associated with LDLc or HDLc. Moreover, targeting glucose metabolism through LDH inhibitor (oxamate) drastically abrogates the cellular proliferation induced by LDLc or HDLc. Collectively, we illustrate the vital role of cholesterol in regulating the cellular glucose and lipid metabolism of cancer cells and its direct effect on the colon tumorigenesis.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"15"},"PeriodicalIF":5.9,"publicationDate":"2023-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10500936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10262498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Positron emission tomography imaging of the sodium iodide symporter senses real-time energy stress in vivo.","authors":"Piotr Dzien, Agata Mackintosh, Gaurav Malviya, Emma Johnson, Dmitry Soloviev, Gavin Brown, Alejandro Huerta Uribe, Colin Nixon, Scott K Lyons, Oliver Maddocks, Karen Blyth, David Y Lewis","doi":"10.1186/s40170-023-00314-2","DOIUrl":"10.1186/s40170-023-00314-2","url":null,"abstract":"<p><strong>Background: </strong>Tissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment.</p><p><strong>Methods: </strong>We modified HEK293T human embryonic kidney cells, and A549 and H358 lung cancer cells to express transgenic NIS. Next, we subjected these cells and implanted tumours to drugs known to induce metabolic stress to observe the impact on NIS activity and energy charge. We used [¹⁸F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo.</p><p><strong>Results: </strong>NIS activity was ablated by treating HEK293T cells in vitro, with the Na⁺/K⁺ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium-potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (- 58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (- 16.6%) in A549 cells in vitro. PET signal was significantly decreased (- 56.5%) within 90 min from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase, and GLUT1 were detectable.</p><p><strong>Conclusions: </strong>NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"14"},"PeriodicalIF":5.9,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10486058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10252904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}