Cancer & Metabolism最新文献

{"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}

{"title":"Scaffold-mediated switching of lymphoma metabolism in culture.","authors":"Rachana Bhatt, Dashnamoorthy Ravi, Andrew M Evens, Biju Parekkadan","doi":"10.1186/s40170-022-00291-y","DOIUrl":"10.1186/s40170-022-00291-y","url":null,"abstract":"<p><strong>Background: </strong>Diffuse large B cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and accounts for about a third of all NHL cases. A significant proportion (~40%) of treated DLBCL patients develop refractory or relapsed disease due to drug resistance which can be attributed to metabolomic and genetic variations amongst diverse DLBCL subtypes. An assay platform that reproduces metabolic patterns of DLBCL in vivo could serve as a useful model for DLBCL.</p><p><strong>Methods: </strong>This report investigated metabolic functions in 2D and 3D cell cultures using parental and drug-resistant DLBCL cell lines as compared to patient biopsy tissue.</p><p><strong>Results: </strong>A 3D culture model controlled the proliferation of parental and drug-resistant DLBCL cell lines, SUDHL-10, SUDHL-10 RR (rituximab resistant), and SUDHL-10 OR (obinutuzumab resistant), as well as retained differential sensitivity to CHOP. The results from metabolic profiling and isotope tracer studies with D-glucose-¹³C₆ indicated metabolic switching in 3D culture when compared with a 2D environment. Analysis of DLBCL patient tumor tissue revealed that the metabolic changes in 3D grown cells were shifted towards that of clinical specimens.</p><p><strong>Conclusion: </strong>3D culture restrained DLBCL cell line growth and modulated metabolic pathways that trend towards the biological characteristics of patient tumors. Counter-intuitively, this research thereby contends that 3D matrices can be a tool to control tumor function towards a slower growing and metabolically dormant state that better reflects in vivo tumor physiology.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"15"},"PeriodicalIF":6.0,"publicationDate":"2022-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9559005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9841008","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 flux analysis of 3D spheroids reveals significant differences in glucose metabolism from matched 2D cultures of colorectal cancer and pancreatic ductal adenocarcinoma cell lines","authors":"Tidwell, Tia R., Røsland, Gro V., Tronstad, Karl Johan, Søreide, Kjetil, Hagland, Hanne R.","doi":"10.1186/s40170-022-00285-w","DOIUrl":"https://doi.org/10.1186/s40170-022-00285-w","url":null,"abstract":"Most in vitro cancer cell experiments have been performed using 2D models. However, 3D spheroid cultures are increasingly favored for being more representative of in vivo tumor conditions. To overcome the translational challenges with 2D cell cultures, 3D systems better model more complex cell-to-cell contact and nutrient levels present in a tumor, improving our understanding of cancer complexity. Despite this need, there are few reports on how 3D cultures differ metabolically from 2D cultures. Well-described cell lines from colorectal cancer (HCT116 and SW948) and pancreatic ductal adenocarcinoma (Panc-1 and MIA-Pa-Ca-2) were used to investigate metabolism in 3D spheroid models. The metabolic variation under normal glucose conditions were investigated comparing 2D and 3D cultures by metabolic flux analysis and expression of key metabolic proteins. We find significant differences in glucose metabolism of 3D cultures compared to 2D cultures, both related to glycolysis and oxidative phosphorylation. Spheroids have higher ATP-linked respiration in standard nutrient conditions and higher non-aerobic ATP production in the absence of supplemented glucose. In addition, ATP-linked respiration is significantly inversely correlated with OCR/ECAR (p = 0.0096). Mitochondrial transport protein, TOMM20, expression decreases in all spheroid models compared to 2D, and monocarboxylate transporter (MCT) expression increases in 3 of the 4 spheroid models. In this study of CRC and PDAC cell lines, we demonstrate that glucose metabolism in 3D spheroids differs significantly from 2D cultures, both in terms of glycolytic and oxidative phosphorylation metrics. The metabolic phenotype shift from 2D to 3D culture in one cell line is greater than the phenotypic differences between each cell line and tumor source. The results herein emphasize the need to use 3D cell models for investigating nutrient utilization and metabolic flux for a better understanding of tumor metabolism and potential metabolic therapeutic targets.","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"34 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138524874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An iron chelation-based combinatorial anticancer therapy comprising deferoxamine and a lactate excretion inhibitor inhibits the proliferation of cancer cells.","authors":"Koichi Fujisawa,&nbsp;Taro Takami,&nbsp;Toshihiko Matsumoto,&nbsp;Naoki Yamamoto,&nbsp;Takahiro Yamasaki,&nbsp;Isao Sakaida","doi":"10.1186/s40170-022-00284-x","DOIUrl":"https://doi.org/10.1186/s40170-022-00284-x","url":null,"abstract":"<p><strong>Background: </strong>Although iron chelation has garnered attention as a novel therapeutic strategy for cancer, higher levels of efficacy need to be achieved. In the present study, we examined the combinatorial effect of deferoxamine (DFO), an iron chelator, and α-cyano-4-hydroxy cinnamate (CHC), a suppressor of lactate excretion, on the proliferation of cancer cell lines.</p><p><strong>Methods: </strong>We established a deferoxamine (DFO)-resistant cell line by culturing HeLa cells in media containing increasing concentrations of DFO. Metabolome and gene expression analyses were performed on these cells. Synergistic effect of the drugs on the cells was determined using an in vitro proliferation assay, and the combination index was estimated.</p><p><strong>Results: </strong>DFO-resistant HeLa cells exhibited enhanced glycolysis, salvage cycle, and de novo nucleic acid synthesis and reduced mitochondrial metabolism. As DFO triggered a metabolic shift toward glycolysis and increased lactate production in cells, we treated the cancer cell lines with a combination of CHC and DFO. A synergistic effect of DFO and CHC was observed in HeLa cells; however, the same was not observed in the human liver cancer cell line Huh7. We hypothesized that the efficacy of the combination therapy in cancer cells depends on the degree of increase in lactate concentration upon DFO treatment.</p><p><strong>Conclusion: </strong>Combination therapy involving administration of DFO and CHC is effective in cancer cells wherein DFO treatment results in an elevation in lactate levels. Our findings illustrate that the DFO-induced enhanced glycolysis provides specific targets for developing an efficient anticancer combinatorial therapy involving DFO. These findings will be beneficial for the development of novel cancer chemotherapeutics.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"8"},"PeriodicalIF":5.9,"publicationDate":"2022-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10253333","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 novel lipid biomarkers in xmrk- and Myc-induced models of hepatocellular carcinoma in zebrafish.","authors":"Jerry D Monroe,&nbsp;Daniel Fraher,&nbsp;Xiaoqian Huang,&nbsp;Natalie A Mellett,&nbsp;Peter J Meikle,&nbsp;Andrew J Sinclair,&nbsp;Seth T Lirette,&nbsp;Nita J Maihle,&nbsp;Zhiyuan Gong,&nbsp;Yann Gibert","doi":"10.1186/s40170-022-00283-y","DOIUrl":"https://doi.org/10.1186/s40170-022-00283-y","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and is accompanied by complex dysregulation of lipids. Increasing evidence suggests that particular lipid species are associated with HCC progression. Here, we aimed to identify lipid biomarkers of HCC associated with the induction of two oncogenes, xmrk, a zebrafish homolog of the human epidermal growth factor receptor (EGFR), and Myc, a regulator of EGFR expression during HCC.</p><p><strong>Methods: </strong>We induced HCC in transgenic xmrk, Myc, and xmrk/Myc zebrafish models. Liver specimens were histologically analyzed to characterize the HCC stage, Oil-Red-O stained to detect lipids, and liquid chromatography/mass spectrometry analyzed to assign and quantify lipid species. Quantitative real-time polymerase chain reaction was used to measure lipid metabolic gene expression in liver samples. Lipid species data was analyzed using univariate and multivariate logistic modeling to correlate lipid class levels with HCC progression.</p><p><strong>Results: </strong>We found that induction of xmrk, Myc and xmrk/Myc caused different stages of HCC. Lipid deposition and class levels generally increased during tumor progression, but triglyceride levels decreased. Myc appears to control early HCC stage lipid species levels in double transgenics, whereas xmrk may take over this role in later stages. Lipid metabolic gene expression can be regulated by either xmrk, Myc, or both oncogenes. Our computational models showed that variations in total levels of several lipid classes are associated with HCC progression.</p><p><strong>Conclusions: </strong>These data indicate that xmrk and Myc can temporally regulate lipid species that may serve as effective biomarkers of HCC progression.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"7"},"PeriodicalIF":5.9,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8981695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10268774","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":"Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.","authors":"Evelyn de Groot, Sruthy Varghese, Lin Tan, Barbara Knighton, Mary Sobieski, Nghi Nguyen, Yong Sung Park, Reid Powell, Philip L Lorenzi, Bin Zheng, Clifford Stephan, Y N Vashisht Gopal","doi":"10.1186/s40170-022-00281-0","DOIUrl":"10.1186/s40170-022-00281-0","url":null,"abstract":"<p><strong>Background: </strong>Primary and posttreatment resistance to BRAF^V600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy.</p><p><strong>Methods: </strong>We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment.</p><p><strong>Results: </strong>A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation.</p><p><strong>Conclusions: </strong>STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"10 1","pages":"6"},"PeriodicalIF":6.0,"publicationDate":"2022-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310509","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":"Bendamustine","authors":"M. Kalaycio","doi":"10.1007/s40278-021-02015-2","DOIUrl":"https://doi.org/10.1007/s40278-021-02015-2","url":null,"abstract":"","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"152 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76783514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}