MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

Lee, Ji Yun; Lee, In Kyoung; Chang, Won Jin; Ahn, Su Min; Lim, Sung Hee; Kim, Hae Su; Yoo, Kwai Han; Jung, Ki Sun; Song, Haa‐Na; Cho, Jin Hyun; Kim, Sun Young; Kim, Kyoung Mee; Lee, Soojin; Park, Se Hoon; Lee, Jeeyun; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki

doi:10.18632/oncotarget.9523

Cited by 48 publications

(37 citation statements)

References 56 publications

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“…In our previous report regarding MCT4 in gastric cancer, MCT4 also was found to be overexpressed in malignant cells in ascites. However, MCT4 expression in gastric cancer was not revealed as a factor for poor prognosis in survival analysis (30). An association between MCT4 expression and poor survival has been reported in pancreas cancer (36) and clear renal cell carcinoma (37); in comparison, here we provide the first report that in patients with colorectal cancer, MCT4 expression instead represents a risk factor for early relapse and shorter RFS.…”

Section: Discussioncontrasting

confidence: 41%

“…We previously studied the clinical implication of MCT4 in metastatic gastric cancer with peritoneal carcinomatosis, which revealed that the inhibition of MCT4 reduced tumor cell proliferation and the export of lactate (30). However, little information is available regarding the relationship between MCT expression and clinical outcome in colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

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MCT4 Expression Is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Kim

Lee

Bang

et al. 2018

Molecular Cancer Therapeutics

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Monocarboxylate transporters (MCT) are transmembrane proteins that control the lactate metabolism and are associated with poor prognosis in solid tumors, including colorectal cancer. Here, we aimed to investigate the biological and clinical role of MCTs in colorectal cancer and to assess the potential of therapeutic application. A total of 16 human colorectal cancer cell lines, 11 patient-derived cells from malignant ascites [patient-derived cells (PDC)], and 39 matched pairs of primary colorectal cancer and normal colorectal tissues were used to assess the role of MCT and siRNA methodology was used to determine the effect of MCT inhibition and molecular mechanism of hypoxia- and angiogenesis-related factors in addition to MCT4. The effect of MCT inhibition was confirmed in mouse xenograft models. MCT4 expression in surgical tissue was evaluated by IHC and used for survival analysis. Expression of MCTs was demonstrated in colorectal cancer cell lines. siRNA-mediated MCT silencing caused significant decline of cell proliferation both and An additive effect of MCT inhibition was induced by combined treatment with chemotherapy or radiotherapy. In particular, the expression of MCT4 was markedly increased in PDCs, and MCT4 inhibition significantly decreased PDC proliferation. Hypoxia-inducible factor 1-α (HIF1α) was also highly expressed in PDCs, whereas HIF1α knockdown reduced MCT4 expression and of other angiogenesis-related mediators. The patients with high MCT4 expression by IHC showed shorter relapse-free survival compared with low expression. These findings suggest that MCT4 may represent a new therapeutic target for colorectal cancer with peritoneal carcinomatosis and serve as a prognostic indicator. .

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Section: Discussioncontrasting

confidence: 41%

Section: Introductionmentioning

confidence: 99%

MCT4 Expression Is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Kim

Lee

Bang

et al. 2018

Molecular Cancer Therapeutics

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“…In an effort to alter lactate transport, small molecule inhibitors have been designed against both MCT1 and MCT4 [91] [92]. Drugs that inhibit mitochondrial OXPHOS are in early phase clinical trials in diseases such as AML, prostate cancer, and colorectal cancer [93] [94] [95].…”

Section: Discussionmentioning

confidence: 99%

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Wilde

Roche

Domingo‐Vidal

et al. 2017

Seminars in Oncology

267

213

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Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation (OXPHOS). Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize OXPHOS. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.

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“…CHC has been suggested to impair glioblastoma cell proliferation, migration, and survival [ 117 ]. AR-C155858 blocks proliferation of gastric cancer cells with high MCT expression in vitro and in vivo in an intraperitoneal injection model in mice [ 118 ]. In most of the studies MCT1 inhibitors are considered to block lactate uptake.…”

Section: Targeting Lipid Metabolism and Therapy Options For Cancermentioning

confidence: 99%

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Sunami

Rebelo

Kleeff

2017

Cancers

126

109

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Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.

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MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

Cited by 48 publications

References 56 publications

MCT4 Expression Is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

MCT4 Expression Is a Potential Therapeutic Target in Colorectal Cancer with Peritoneal Carcinomatosis

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

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