Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

Hu, Ke; Wang, De Gui; Liu, Peng Fei; Cao, Yan; Wang, Yong Hua; Yang, Xue; Hu, Cheng; Sun, Li; Niu, Hai

doi:10.3892/or.2016.4884

Cited by 27 publications

(24 citation statements)

References 36 publications

(35 reference statements)

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“…Our previous studies revealed a series of changes of metabolic reprogramming in the context of tumor microenvironment. We found that CAFs and tumor endothelial cells in tumor microenvironment played an important role in cancer glycolysis and progression 11 , 20 . Targeting MCT1 in CAFs and tumor endothelial cells regulated BCa cell growth and apoptosis by altering the tumor microenvironment 20 .…”

Section: Discussionmentioning

confidence: 89%

“…We found that CAFs and tumor endothelial cells in tumor microenvironment played an important role in cancer glycolysis and progression 11 , 20 . Targeting MCT1 in CAFs and tumor endothelial cells regulated BCa cell growth and apoptosis by altering the tumor microenvironment 20 . The present study found that knockdown of MCT1 in BCa cells significantly inhibited cell proliferation in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 89%

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MCT1 regulates aggressive and metabolic phenotypes in bladder cancer

Zhang¹,

Zhang²,

Dong³

et al. 2018

J. Cancer

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Background: Monocarboxylate transporter isoform 1 (MCT1) is an important molecule in mediating lactate transportation. Recent studies have shown an oncogenic role of MCT1 in cancer development.Methods: In this study, we aimed to investigate the expression and role of MCT1 in bladder cancer (BCa). MCT1 expression was detected in 124 BCa tissues and their clinicopathological significance was analyzed. We also used The Cancer Genome Atlas database to explore the prognostic association of MCT1 with BCa. Cell proliferation, migration and invasion assays were performed on BCa cells in which MCT1 was downregulated. The effect of MCT1 on BCa cell aerobic glycolysis, as well as its association with HIF-1α, was tested.Results: We found that high MCT1 expression correlated with lymph node and distant metastasis. Patients with high-MCT1 expression showed shorter overall survival than those with low-MCT1 expression. Knockdown of MCT1 inhibited BCa cell proliferation, migration and invasion, and affected expression of epithelial-mesenchymal transition related proteins. Downregulation of MCT1 decreased lactate levels in cell medium, as well as HK2, GLUT1 and LDHB expression. In addition, MCT1 expression was partly dependent on HIF-1α.Conclusions: Taken together, our study has shown a prognostic role of MCT1 in BCa, and provided potential diagnostic and therapeutic options for BCa patients.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 89%

MCT1 regulates aggressive and metabolic phenotypes in bladder cancer

Zhang¹,

Zhang²,

Dong³

et al. 2018

J. Cancer

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“…PFKFB3, a member of the PFKFB family, has a significantly high kinase activity, enhances the F2,6BP level and glycolysis effect ( 12 ). The protein levels of PFKFB3 are commonly elevated in various types of human cancer, including breast ( 13 ), gastric ( 14 ) and bladder cancer ( 15 ). In addition, previous studies have demonstrated that the inhibition of PFKFB3 was able to suppress the glucose metabolism and cell proliferation in cancer cells ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

PFK15, a PFKFB3 antagonist, inhibits autophagy and proliferation in rhabdomyosarcoma cells

Wang

Yan

et al. 2018

Int J Mol Med

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Due to the high-level of metastatic and relapsed rates, rhabdomyosarcoma (RD) patients have a poor prognosis, and novel treatment strategies are required. Thereby, the present study evaluated the efficacy of PFK15, a PFKFB3 inhibitor, in RD cells to explore its potential underlying mechanism on the regulation of autophagy and proliferation in these cells. The effects of PFK15 on cell viability loss and cell death in different treatment groups, were evaluated by MTS assay, colony growth assay and immunoblotting, respectively. In addition, the autophagy levels were detected by electron microscopy, fluorescence microscopy and immunoblotting following PFK15 treatment, and the autophagic flux was analyzed with the addition of chloroquine diphosphate salt or by monitoring the level of p62. PFK15 was observed to evidently decrease the viability of RD cells, inhibit the colony growth and cause abnormal nuclear morphology. Furthermore, PFK15 inhibited the autophagic flux and cell proliferation, as well as induced apoptotic cell death in RD cells through downregulation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. An AMPK agonist rescued the inhibited cell proliferation and autophagy induced by PFK15. In conclusion, PFK15 inhibits autophagy and cell proliferation via downregulating the AMPK signaling pathway in RD cells.

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“…These results are interesting and unexpected. When tumor cells coexist with vascular endothelial cells in hypoxic and acidic environments, the energy metabolic pathway of glycolysis is activated, which is critical for tumor growth and angiogenesis [12]. Glycolysis is enhanced by MCT1 and MCT4, and therefore, reprogramming of glucose metabolism occurs [11].…”

Section: Discussionmentioning

confidence: 99%

“…The Warburg effect describes a new metabolic way in which most cancer cells function utilizing energy generated from efficient glycolysis followed by the fermentation of lactic acid and acidification [12, 13]. Enhanced glycolysis is tightly associated with tumorigenesis and metastasis [13].…”

Section: Introductionmentioning

confidence: 99%

Monocarboxylate transporter 1 and monocarboxylate transporter 4 in cancer-endothelial co-culturing microenvironments promote proliferation, migration, and invasion of renal cancer cells

et al. 2019

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Background The Warburg effect demonstrates the importance of glycolysis in the development of primary and metastatic cancers. We aimed to explore the role of monocarboxylate transporter 1 (MCT1) and MCT4, two essential transporters of lactate, in renal cancer progression during cancer-endothelial cell co-culturing. Methods Renal cancer cells (786-O) and human vascular endothelial cells (HUVECs) were single-cultured or co-cultured in transwell membranes in the presence or absence of a MCT-1/MCT-4 specific blocker, 7ACC1. Cell proliferation was evaluated with the CCK-8 kit, while cell migration, after a scratch and invasion in transwell chambers, was evaluated under a microscope. Real-time qPCR and western blot were employed to determine the mRNA and protein levels of MCT1 and MCT4, respectively. The concentration of lactic acid in the culture medium was quantified with an l -Lactic Acid Assay Kit. Results 786-O cells and HUVECs in the co-culturing mode exhibited significantly enhanced proliferation and migration ability, compared with the cells in the single-culturing mode. The expression of MCT1 and MCT4 was increased in both 786-O cells and HUVECs in the co-culturing mode. Co-culturing promoted the invasive ability of 786-O cells, and markedly increased extracellular lactate. Treatments with 7ACC1 attenuated cell proliferation, migration, and invasion, and down-regulated the levels of MCT1/MCT4 expression and extracellular lactate. Conclusions The Warburg effect accompanied with high MCT1/MCT4 expression in the cancer-endothelial microenvironments contributed significantly to renal cancer progression, which sheds new light on targeting MCT1/MCT4 and glycolytic metabolism in order to effectively treat patients with renal cancers.

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Targeting of MCT1 and PFKFB3 influences cell proliferation and apoptosis in bladder cancer by altering the tumor microenvironment

Cited by 27 publications

References 36 publications

MCT1 regulates aggressive and metabolic phenotypes in bladder cancer

MCT1 regulates aggressive and metabolic phenotypes in bladder cancer

PFK15, a PFKFB3 antagonist, inhibits autophagy and proliferation in rhabdomyosarcoma cells

Monocarboxylate transporter 1 and monocarboxylate transporter 4 in cancer-endothelial co-culturing microenvironments promote proliferation, migration, and invasion of renal cancer cells

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