Cancer & Metabolism最新文献

{"title":"Breast cancer cells that preferentially metastasize to lung or bone are more glycolytic, synthesize serine at greater rates, and consume less ATP and NADPH than parent MDA-MB-231 cells.","authors":"Mika B Jekabsons,&nbsp;Mollie Merrell,&nbsp;Anna G Skubiz,&nbsp;Noah Thornton,&nbsp;Sandra Milasta,&nbsp;Douglas Green,&nbsp;Taosheng Chen,&nbsp;Yan-Hong Wang,&nbsp;Bharathi Avula,&nbsp;Ikhlas A Khan,&nbsp;Yu-Dong Zhou","doi":"10.1186/s40170-023-00303-5","DOIUrl":"https://doi.org/10.1186/s40170-023-00303-5","url":null,"abstract":"<p><p>Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. However, since pathway fluxes depend on additional factors such as ATP demand, allosteric effects, and post-translational modification, flux analysis is necessary to conclusively establish phenotypes. In this study, the metabolic phenotypes of breast cancer cell lines with low (T47D) or high (MDA-MB-231) metastatic potential, as well as lung (LM)- and bone (BoM)-homing lines derived from MDA-MB-231 cells, were assessed by ¹³C metabolite labeling from [1,2-¹³C] glucose or [5-¹³C] glutamine and the rates of nutrient and oxygen consumption and lactate production. MDA-MB-231 and T47D cells produced 55 and 63%, respectively, of ATP from oxidative phosphorylation, whereas LM and BoM cells were more glycolytic, deriving only 20-25% of their ATP from mitochondria. ATP demand by BoM and LM cells was approximately half the rate of the parent cells. Of the anabolic fluxes assessed, nucleotide synthesis was the major ATP consumer for all cell lines. Glycolytic NADH production by LM cells exceeded the rate at which it could be oxidized by mitochondria, suggesting that the malate-aspartate shuttle was not involved in re-oxidation of these reducing equivalents. Serine synthesis was undetectable in MDA-MB-231 cells, whereas 3-5% of glucose was shunted to serine by LM and BoM lines. Proliferation rates of T47D, BoM, and LM lines tightly correlated with their respiration-normalized NADPH production rates. In contrast, MDA-MB-231 cells produced NADPH and GSH at higher rates, suggesting this line is more oxidatively stressed. Approximately half to two-thirds of NADPH produced by T47D, MDA-MB-231, and BoM cells was from the oxidative PPP, whereas the majority in LM cells was from the folate cycle. All four cell lines used the non-oxidative PPP to produce pentose phosphates, although this was most prominent for LM cells. Taken together, the metabolic phenotypes of LM and BoM lines differed from the parent line and from each other, supporting the metabolic re-wiring hypothesis as a feature of metastasis to lung and bone.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"4"},"PeriodicalIF":5.9,"publicationDate":"2023-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10149147","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":"Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer.","authors":"F V Reinema, F C G J Sweep, G J Adema, W J M Peeters, J W M Martens, J Bussink, P N Span","doi":"10.1186/s40170-023-00304-4","DOIUrl":"10.1186/s40170-023-00304-4","url":null,"abstract":"<p><strong>Background: </strong>Recently, we reported that tamoxifen-resistant (TAM-R) breast cancer cells are cross-resistant to irradiation. Here, we investigated the mechanisms associated with tamoxifen-induced radioresistance, aiming to prevent or reverse resistance and improve breast cancer treatment.</p><p><strong>Methods: </strong>Wild-type ERα-positive MCF7 and ERα-negative MDA-MB-231 breast cancer cells and their TAM-R counterparts were analyzed for cellular metabolism using the Seahorse metabolic analyzer. Real-time ROS production, toxicity, and antioxidant capacity in response to H₂O₂, tamoxifen, and irradiation were determined. Tumor material from 28 breast cancer patients before and after short-term presurgical tamoxifen (ClinicalTrials.gov Identifier: NCT00738777, August 19, 2008) and cellular material was analyzed for NRF2 gene expression and immunohistochemistry. Re-sensitization of TAM-R cells to irradiation was established using pharmacological inhibition.</p><p><strong>Results: </strong>TAM-R cells exhibited decreased oxygen consumption and increased glycolysis, suggesting mitochondrial dysfunction. However, this did not explain radioresistance, as cells without mitochondria (Rho-0) were actually more radiosensitive. Real-time measurement of ROS after tamoxifen and H₂O₂ exposure indicated lower ROS levels and toxicity in TAM-R cells. Consistently, higher antioxidant levels were found in TAM-R cells, providing protection from irradiation-induced ROS. NRF2, a main activator of the antioxidant response, was increased in TAM-R cells and in tumor tissue of patients treated with short-term presurgical tamoxifen. NRF2 inhibition re-sensitized TAM-R cells to irradiation.</p><p><strong>Conclusion: </strong>Mechanisms underlying tamoxifen-induced radioresistance are linked to cellular adaptations to persistently increased ROS levels, leading to cells with chronically upregulated antioxidant capacity and glycolysis. Pharmacological inhibition of antioxidant responses re-sensitizes breast cancer cells to irradiation.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"3"},"PeriodicalIF":6.0,"publicationDate":"2023-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9909892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10684458","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":"Metabolic profiling reveals metabolic features of consolidation therapy in pediatric acute lymphoblastic leukemia.","authors":"Jinqiu Fu,&nbsp;Aijun Zhang,&nbsp;Qinqin Liu,&nbsp;Dong Li,&nbsp;Xiaoming Wang,&nbsp;Libo Si","doi":"10.1186/s40170-023-00302-6","DOIUrl":"https://doi.org/10.1186/s40170-023-00302-6","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) and its treatment continue to pose substantial risks. To understand ALL more deeply, the metabolome in fasting plasma of 27 ALL patients before and after high-dose methotrexate therapies (consolidation therapy) including methotrexate and 6-mercaptopurine (6-MP) was investigated. Plasma metabolites were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS). Orthogonal projections to latent structures discriminant analysis and significance analysis of microarrays were used to evaluate the metabolic changes. Pathway enrichment and co-expression network analyses were performed to identify clusters of molecules, and 2826 metabolites were identified. Among them, 38 metabolites were identified by univariate analysis, and 7 metabolites that were altered by conditioning therapy were identified by multivariate analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used for pathway enrichment analysis. Among the enriched KEGG pathways, the 3 significantly altered metabolic pathways were pyrimidine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. In addition, L-phenylalanine was significantly correlated with blood urea nitrogen (BUN), and palmitoylcarnitine was correlated with aspartate aminotransferase (AST). In summary, consolidation therapy significantly affected pyrimidine- and phenylalanine-associated metabolic pathways in pediatric ALL patients. These findings may provide an insight into the role of metabolic profiling in consolidation treatment and as a potential for pediatric ALL patients.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"2"},"PeriodicalIF":5.9,"publicationDate":"2023-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9869545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10667406","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":"Arginase-1 inhibition reduces migration ability and metastatic colonization of colon cancer cells.","authors":"Xiangdong Wang,&nbsp;Huihui Xiang,&nbsp;Yujiro Toyoshima,&nbsp;Weidong Shen,&nbsp;Shunsuke Shichi,&nbsp;Hiroki Nakamoto,&nbsp;Saori Kimura,&nbsp;Ko Sugiyama,&nbsp;Shigenori Homma,&nbsp;Yohei Miyagi,&nbsp;Akinobu Taketomi,&nbsp;Hidemitsu Kitamura","doi":"10.1186/s40170-022-00301-z","DOIUrl":"https://doi.org/10.1186/s40170-022-00301-z","url":null,"abstract":"<p><strong>Background: </strong>Arginase-1 (ARG1), a urea cycle-related enzyme, catalyzes the hydrolysis of arginine to urea and ornithine, which regulates the proliferation, differentiation, and function of various cells. However, it is unclear whether ARG1 controls the progression and malignant alterations of colon cancer.</p><p><strong>Methods: </strong>We established metastatic colonization mouse model and ARG1 overexpressing murine colon cancer CT26 cells to investigate whether activation of ARG1 was related to malignancy of colon cancer cells in vivo. Living cell numbers and migration ability of CT26 cells were evaluated in the presence of ARG inhibitor in vitro.</p><p><strong>Results: </strong>Inhibition of arginase activity significantly suppressed the proliferation and migration ability of CT26 murine colon cancer cells in vitro. Overexpression of ARG1 in CT26 cells reduced intracellular L-arginine levels, enhanced cell migration, and promoted epithelial-mesenchymal transition. Metastatic colonization of CT26 cells in lung and liver tissues was significantly augmented by ARG1 overexpression in vivo. ARG1 gene expression was higher in the tumor tissues of liver metastasis than those of primary tumor, and arginase inhibition suppressed the migration ability of HCT116 human colon cancer cells.</p><p><strong>Conclusion: </strong>Activation of ARG1 is related to the migration ability and metastatic colonization of colon cancer cells, and blockade of this process may be a novel strategy for controlling cancer malignancy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"1"},"PeriodicalIF":5.9,"publicationDate":"2023-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9838026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9080180","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":"Functional noninvasive detection of glycolytic pancreatic ductal adenocarcinoma.","authors":"Irina Heid,&nbsp;Corinna Münch,&nbsp;Sinan Karakaya,&nbsp;Smiths S Lueong,&nbsp;Alina M Winkelkotte,&nbsp;Sven T Liffers,&nbsp;Laura Godfrey,&nbsp;Phyllis F Y Cheung,&nbsp;Konstantinos Savvatakis,&nbsp;Geoffrey J Topping,&nbsp;Florian Englert,&nbsp;Lukas Kritzner,&nbsp;Martin Grashei,&nbsp;Andrea Tannapfel,&nbsp;Richard Viebahn,&nbsp;Heiner Wolters,&nbsp;Waldemar Uhl,&nbsp;Deepak Vangala,&nbsp;Esther M M Smeets,&nbsp;Erik H J G Aarntzen,&nbsp;Daniel Rauh,&nbsp;Wilko Weichert,&nbsp;Jörg D Hoheisel,&nbsp;Stephan A Hahn,&nbsp;Franz Schilling,&nbsp;Rickmer Braren,&nbsp;Marija Trajkovic-Arsic,&nbsp;Jens T Siveke","doi":"10.1186/s40170-022-00298-5","DOIUrl":"https://doi.org/10.1186/s40170-022-00298-5","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatment options beyond chemotherapy. Although molecular subtypes such as classical and QM (quasi-mesenchymal)/basal-like with transcriptome-based distinct signatures have been identified, deduced therapeutic strategies and targets remain elusive. Gene expression data show enrichment of glycolytic genes in the more aggressive and therapy-resistant QM subtype. However, whether the glycolytic transcripts are translated into functional glycolysis that could further be explored for metabolic targeting in QM subtype is still not known.</p><p><strong>Methods: </strong>We used different patient-derived PDAC model systems (conventional and primary patient-derived cells, patient-derived xenografts (PDX), and patient samples) and performed transcriptional and functional metabolic analysis. These included RNAseq and Illumina HT12 bead array, in vitro Seahorse metabolic flux assays and metabolic drug targeting, and in vivo hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate magnetic resonance spectroscopy (HP-MRS) in PDAC xenografts.</p><p><strong>Results: </strong>We found that glycolytic metabolic dependencies are not unambiguously functionally exposed in all QM PDACs. Metabolic analysis demonstrated functional metabolic heterogeneity in patient-derived primary cells and less so in conventional cell lines independent of molecular subtype. Importantly, we observed that the glycolytic product lactate is actively imported into the PDAC cells and used in mitochondrial oxidation in both classical and QM PDAC cells, although more actively in the QM cell lines. By using HP-MRS, we were able to noninvasively identify highly glycolytic PDAC xenografts by detecting the last glycolytic enzymatic step and prominent intra-tumoral [1-¹³C]pyruvate and [1-¹³C]lactate interconversion in vivo.</p><p><strong>Conclusion: </strong>Our study adds functional metabolic phenotyping to transcriptome-based analysis and proposes a functional approach to identify highly glycolytic PDACs as candidates for antimetabolic therapeutic avenues.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"24"},"PeriodicalIF":5.9,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10329732","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":"PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer.","authors":"Wan-Hsuan Sun,&nbsp;Yun-Hsuan Chen,&nbsp;Hou-Hsuan Lee,&nbsp;Yu-Wen Tang,&nbsp;Kuang-Hui Sun","doi":"10.1186/s40170-022-00300-0","DOIUrl":"https://doi.org/10.1186/s40170-022-00300-0","url":null,"abstract":"<p><strong>Background: </strong>Resistance to chemotherapeutic drugs is a key factor for cancer recurrence and metastases in head and neck cancer (HNC). Cancer stem cells (CSCs) in tumors have self-renewal, differentiation, and higher drug resistance capabilities, resulting in a poor prognosis for patients. In glucose metabolism, pyruvate dehydrogenase kinase (PDK) inhibits pyruvate dehydrogenase and impedes pyruvate from being metabolized into acetyl-CoA and entering the tricarboxylic acid cycle to generate energy. Studies have reported that PDK1 and PDK2 inhibition suppresses the growth, motility, and drug resistance of cancer cells. Furthermore, while TGFβ1 levels are persistently elevated in HNC patients with poor prognosis, the role of PDK isoforms in the TGFβ1-promoted progression and stem-like properties of HNC is unclear.</p><p><strong>Methods: </strong>Levels of PDK1 and PDK2 were evaluated in HNC tissue microarrays by immunohistochemistry to explore potential clinical relevance. PDK1 and PDK2 were knocked down by the lentivirus shRNA system to investigate their role in TGFβ1-promoted tumor progression in vitro.</p><p><strong>Results: </strong>We found that PDK2 levels were increased in the later stage of HNC tissues compared to constant PDK1 expression. After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFβ1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFβ1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance.</p><p><strong>Conclusion: </strong>The results demonstrated that the PDK1- and PDK2-mediated Warburg effect contributes to the TGFβ1-enhanced stemness properties of HNC. Therefore, PDK1 and PDK2 may serve as molecular targets for the combination therapy of HNC.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"23"},"PeriodicalIF":5.9,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10430523","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":"Tadalafil increases the antitumor activity of 5-FU through inhibiting PRMT5-mediated glycolysis and cell proliferation in colorectal cancer.","authors":"Yao Shen,&nbsp;Pan Zhao,&nbsp;Kewei Dong,&nbsp;Jiajia Wang,&nbsp;Huichen Li,&nbsp;Mengyang Li,&nbsp;Ruikai Li,&nbsp;Suning Chen,&nbsp;Yuxia Shen,&nbsp;Zhiyu Liu,&nbsp;Mianjiao Xie,&nbsp;Peng Shen,&nbsp;Jian Zhang","doi":"10.1186/s40170-022-00299-4","DOIUrl":"https://doi.org/10.1186/s40170-022-00299-4","url":null,"abstract":"<p><strong>Background: </strong>Protein arginine methyltransferase 5 (PRMT5) is upregulated in multiple tumors and plays a pivotal role in cancer cell proliferation. However, the role of PRMT5 in colorectal cancer remains poorly understood.</p><p><strong>Methods: </strong>We detected the expression level of PRMT5 and glycolytic enzymes using online databases and colorectal cancer cell lines by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blotting. And MTT and colony formation assays were conducted to investigate cell proliferation. Then, we evaluated ECAR and OCR levels using a biological energy analyzer to investigate the energy status of colorectal cancer, and the transcriptional regulation was detected by dual luciferase reporter assay and ChIP assay. Finally, the efficacy of combined treatment of tadalafil and 5-FU was verified.</p><p><strong>Results: </strong>PRMT5 was highly expressed in colorectal cancer tissues compared with their normal counterparts and correlated with poor prognosis in CRC patients. Then, we demonstrated that PRMT5 knockdown or loss of function attenuated the viability of CRC cells, while overexpression of PRMT5 promoted cell proliferation. Mechanistically, PRMT5 enhanced glycolysis through transcriptionally activating LDHA expression. In addition, the PRMT5 inhibitor, tadalafil, rendered CRC cells sensitive to antitumor agent 5-FU in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our data indicates that PRMT5 promoted colorectal cancer proliferation partially through activating glycolysis and may be a potential target for colorectal cancer therapy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"22"},"PeriodicalIF":5.9,"publicationDate":"2022-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9727889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10719378","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":"Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity.","authors":"Xinyi Zhang,&nbsp;Alexandra A Halberstam,&nbsp;Wanling Zhu,&nbsp;Brooks P Leitner,&nbsp;Durga Thakral,&nbsp;Marcus W Bosenberg,&nbsp;Rachel J Perry","doi":"10.1186/s40170-022-00296-7","DOIUrl":"https://doi.org/10.1186/s40170-022-00296-7","url":null,"abstract":"<p><strong>Background: </strong>Research about tumor \"metabolic flexibility\"-the ability of cells to toggle between preferred nutrients depending on the metabolic context-has largely focused on obesity-associated cancers. However, increasing evidence for a key role for nutrient competition in the tumor microenvironment, as well as for substrate regulation of immune function, suggests that substrate metabolism deserves reconsideration in immunogenic tumors that are not strongly associated with obesity.</p><p><strong>Methods: </strong>We compare two murine models: immunologically cold YUMM1.7 and immunologically-hot YUMMER1.7. We utilize stable isotope and radioisotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics analyses to comprehensively probe substrate preference in YUMM1.7 and YUMMER1.7 cells, with a subset of studies on the impact of available metabolites across a panel of five additional melanoma cell lines. We analyze bulk RNA-seq data and identify increased expression of amino acid and glucose metabolism genes in YUMMER1.7. Finally, we analyze melanoma patient RNA-seq data to identify potential prognostic predictors rooted in metabolism.</p><p><strong>Results: </strong>We demonstrate using stable isotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics that immunologically-hot melanoma utilizes more glutamine than immunologically-cold melanoma in vivo and in vitro. Analyses of human melanoma RNA-seq data demonstrate that glutamine transporter and other anaplerotic gene expression positively correlates with lymphocyte infiltration and function.</p><p><strong>Conclusions: </strong>Here, we highlight the importance of understanding metabolism in non-obesity-associated cancers, such as melanoma. This work advances the understanding of the correlation between metabolism and immunogenicity in the tumor microenvironment and provides evidence supporting metabolic gene expression as potential prognostic factors of melanoma progression and may inform investigations of adjunctive metabolic therapy in melanoma.</p><p><strong>Trial registration: </strong>Deidentified data from The Cancer Genome Atlas were analyzed.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"21"},"PeriodicalIF":5.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10061099","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":"Blocking lncRNA-SNHG16 sensitizes gastric cancer cells to 5-Fu through targeting the miR-506-3p-PTBP1-mediated glucose metabolism.","authors":"Yan Ding,&nbsp;Sujie Gao,&nbsp;Jiabin Zheng,&nbsp;Xuebo Chen","doi":"10.1186/s40170-022-00293-w","DOIUrl":"https://doi.org/10.1186/s40170-022-00293-w","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is a commonly occurring human malignancy. The 5-fluorouracil (5-Fu) is a first-line anti-gastric cancer agent. However, a large number of GC patients developed 5-Fu resistance. Currently, the roles and molecular mechanisms of the lncRNA-SNHG16-modulated 5-Fu resistance in gastric cancer remain elusive.</p><p><strong>Methods: </strong>Expressions of lncRNA, miRNA, and mRNA were detected by qRT-PCR and Western blot. RNA-RNA interaction was examined by RNA pull-down and luciferase assay. Cell viability and apoptosis rate under 5-Fu treatments were determined by MTT assay and Annexin V assay. The glycolysis rate of GC cells was evaluated by glucose uptake and ECAR.</p><p><strong>Results: </strong>Here, we report that SNHG16 as well as PTBP1, which is an RNA-binding protein, are positively associated with 5-Fu resistance to gastric cancer. SNHG16 and PTBP1 were significantly upregulated in gastric tumors and cell lines. Silencing SNHG16 or PTBP1 effectively sensitized GC cells to 5-Fu. Furthermore, glucose metabolism was remarkedly elevated in 5-Fu-resistant GC cells. Under low glucose supply, 5-Fu-resistant cells displayed higher vulnerability than parental GC cells. Bioinformatic analysis and luciferase assay demonstrated that SNHG16 downregulated miR-506-3p by sponging it to form a ceRNA network. We identified PTBP1 as a direct target of miR-506-3p in GC cells. RNA-seq results unveiled that PTBP1 positively regulated expressions of multiple glycolysis enzymes, including GLUT1, HK2, and LDHA. Bioinformatic analysis illustrated the 3'UTRs of glycolysis enzymes contained multiple PTBP1 binding sites, which were further verified by RNA pull-down and RNA immunoprecipitation assays. Consequently, we demonstrated that PTBP1 upregulated the mRNAs of glycolysis enzymes via promoting their mRNA stabilities. Finally, in vivo xenograft experiments validated that blocking the SNHG16-mediated miR-506-3p-PTBP1 axis effectively limited 5-Fu-resistant GC cell originated-xenograft tumor growth under 5-Fu treatments.</p><p><strong>Conclusions: </strong>Our study demonstrates molecular mechanisms of the SNHG16-mediated 5-Fu resistance of GC cells through modulating the miR-506-3p-PTBP1-glucose metabolism axis, presenting a promising approach for anti-chemoresistance therapy.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"20"},"PeriodicalIF":5.9,"publicationDate":"2022-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9707261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10694564","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":"Altered acetyl-CoA metabolism presents a new potential immunotherapy target in the obese lung microenvironment.","authors":"Spencer R Rosario,&nbsp;Randall J Smith,&nbsp;Santosh K Patnaik,&nbsp;Song Liu,&nbsp;Joseph Barbi,&nbsp;Sai Yendamuri","doi":"10.1186/s40170-022-00292-x","DOIUrl":"https://doi.org/10.1186/s40170-022-00292-x","url":null,"abstract":"<p><p>Contrary to the \"obesity paradox,\" which arises from retrospective studies relying on body mass index to define obesity, epidemiologic evidence suggests central or visceral obesity is associated with a higher risk for the development of lung cancer. About 60% of individuals at high risk for developing lung cancer or those already with early-stage disease are either overweight or obese. Findings from resected patient tumors and mouse lung tumor models show obesity dampens immune activity in the tumor microenvironment (TME) encouraging disease progression. In line with this, we have observed a marked, obesity-specific enhancement in the presence and phenotype of immunosuppressive regulatory T (Treg) cells in murine tumors as well as the airways of both humans and mice. Leveraging direct metabolomic measurements and robust inferred analyses from RNA-sequencing data, we here demonstrate for the first time that visceral adiposity alters the lung microenvironment via dysregulated acetyl-CoA metabolism in a direction that facilitates immune suppression and lung carcinogenesis.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"17"},"PeriodicalIF":5.9,"publicationDate":"2022-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9620073","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}