Overexpression of monocarboxylate transporter 4 promotes the migration and invasion of non‑carcinogenic L929 fibroblast cells

Li, Xiangru; Zhou, Xingyao; Liu, Ying; Fan, Jingjing; Huo, Hongjing; Yao, Jiayi; Wang, Lin; Ma, Ningning

doi:10.3892/ol.2020.12305

Cited by 4 publications

(5 citation statements)

References 36 publications

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“…Confirming and extending earlier reports by us and others ( Gallagher et al, 2009 ; Kong et al, 2016 ; Zhu et al, 2014 ; Andersen et al, 2018 ), we next showed that MDA-MB-231 cell migration and invasion were attenuated by KD of either MCT4 or CD147, and conversely, were increased by their OE. These effects at least in part involve the transport activity of MCT4, as inhibition of monocarboxylate transporters ( Kong et al, 2016 ) or an MCT4 mutation abolishing transport ( Li et al, 2021 ) attenuate cancer cell migration and invasion. A role for MCT4 interaction with integrins has been proposed to contribute to the role of the transporter in cell migration, based on co-immunoprecipitation and colocalization to the leading edge ( Gallagher et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells

Meng,

Sørensen,

Ponniah

et al. 2024

Journal of Cell Science

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The lactate-proton cotransporter MCT4 and its chaperone CD147 are upregulated in breast cancers, correlating with decreased patient survival. Here, we test the hypothesis that MCT4 and CD147 favor breast cancer invasion through interdependent effects on extracellular matrix (ECM) degradation. MCT4 and CD147 expression and membrane localization were strongly reciprocally interdependent in MDA-MB-231 breast cancer cells. Knockdown (KD) and overexpression (OE) of MCT4 and/or CD174 in- and decreased, respectively, migration, invasion, and fluorescent gelatin degradation. OE of both proteins increased gelatin degradation and appearance of the matrix metalloprotease (MMP)-generated collagen-I cleavage product reC1M more than each protein alone, suggesting a concerted role in ECM degradation. MCT4 and CD147 co-localized with invadopodia markers at the plasma membrane and with MMP14, the lysosomal marker LAMP-1, and partially with the autophagosome marker LC3, in F-actin-decorated intracellular vesicles. We conclude that MCT4 and CD147 reciprocally regulate each other and interdependently support migration and invasiveness of MDA-MB-231 breast cancer cells. Mechanistically, this involves MCT4-CD147-dependent stimulation of ECM degradation and specifically of MMP-mediated collagen-I degradation. We suggest that the MCT4-CD147 complex is co-delivered to invadopodia with MMP14.

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Section: Discussionmentioning

confidence: 99%

MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells

Meng,

Sørensen,

Ponniah

et al. 2024

Journal of Cell Science

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“…These findings are from studies in which MCT4 was silenced in one type of tumor cell, and the mechanism by which MCT4 promotes migration varies among the different tumor cell models. Silencing may sometimes be transient or incomplete; however, in our previous study, MCT4-L929 cell lines were generated by stable transfection and it was demonstrated that MCT4 promotes the migration and invasion of non-cancerous L929 cells ( 24 ). Therefore, it is suggested that the upregulated expression of MCT4 may promote the carcinogenesis of L929 cells.…”

Section: Discussionmentioning

confidence: 99%

“…L929 cells, which are non-cancerous murine cells that do not express MCT4, were obtained from the American Type Culture Collection (ATCC). L929 cell lines stably expressing human MCT4 were constructed as previously described ( 24 ). The human SLC16A3 gene sequence and enhanced green fluorescent protein (EGFP) gene sequence were inserted into a pcDNA3.0 vector, and the plasmids were transfected into host L929 cells by electroporation.…”

Section: Methodsmentioning

confidence: 99%

“…Few studies have investigated the mechanism by which MCT4 promotes cell migration, and the mechanism by which MCT4 promotes migration has been found to vary, with inconsistency between different tumor cell models. In our previous study, human MCT4 was expressed in non-cancerous L929 cells via stable transfection and the overexpression of MCT4 was demonstrated to promote the migration and invasion of the non-cancerous L929 fibroblast cells ( 24 ). Notably, the homology of human and mouse MCT4 proteins is as high as 88%.…”

Section: Introductionmentioning

confidence: 99%

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Monocarboxylate transporter 4 promotes the migration of non‑cancerous L929 fibroblast cells by activating the IGF1/IGF1R/PIK3R3/SGK1 axis

Zhou,

Wang,

et al. 2023

Oncol Lett

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The tumor microenvironment (TME) and Warburg effect are critical for the regulation of tumor metastasis. The monocarboxylate transporter (MCT) family members, particularly MCT4, which is encoded by the solute carrier family 16 member 3 gene, play an important role in the regulation of the TME and mediation of the Warburg effect by transporting lactate out of cancer cells. Migration and invasion are two key features of metastasis. Few studies have investigated the mechanism by which MCT4 promotes cell migration, and the suggested mechanisms by which MCT4 promotes migration vary in different tumor cell models. The purpose of the present study was to use non-cancerous cells as a research model to investigate the specific mechanism underlying the promotion of migration by MCT4. In a previous study, murine L929 cells overexpressing human MCT4 (MCT4-L929 cells) were generated and MCT4 was demonstrated to promote the migration and invasion of these non-cancerous cells. In the present study, MCT4-L929 cells and control-L929 cells were used to investigate the potential pathways and mechanisms through which MCT4 promotes cell migration. RNA sequencing analysis revealed 872 differentially expressed genes, comprising 337 and 535 upregulated and downregulated genes, respectively, in the MCT4-L929 cells. Reverse transcription-quantitative analysis and western blotting revealed that MCT4 overexpression increased the transcription and protein levels of insulin-like growth factor 1 (IGF1). In a wound healing assay, the migration of exogenous mouse IGF1-treated control-L929 cells was similar to that of MCT4-L929 cells. Additionally, the inhibition of IGF1 receptor (IGF1R) or serum/glucocorticoid regulated kinase 1 (SGK1), a downstream protein in the IGF1 and phosphoinositide 3-kinase PI3K regulatory subunit 3 (PIK3R3) pathways, in MCT4-L929 cells mitigated the cell migration-promoting effect of MCT4. These novel findings suggest that MCT4 may promote the migration of L929 fibroblast cells via activation of the IGF1/IGF1R/PIK3R3/SGK1 axis.

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“…Some studies have used the non-tumorigenic mouse NCTC clone 929 (L929) cell line to express endogenous MCT1 and MCT4 and transfect MCT1 and MCT4, respectively. The results showed that overexpression of MCT4, but not MCT1, promoted the migration and invasion of L929 cells ( Li et al, 2021 ). MCT4 can also promote the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of liver cancer cells by upregulating the transport protein particle complex subunit 5 (TRAPPC5) gene ( Niu et al, 2022 ).…”

Section: Mct and Metastasismentioning

confidence: 99%

Proton-coupled monocarboxylate transporters in cancer: From metabolic crosstalk, immunosuppression and anti-apoptosis to clinical applications

Duan

Zhang

Wang

et al. 2022

Front. Cell Dev. Biol.

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The Warburg effect is known as the hyperactive glycolysis that provides the energy needed for rapid growth and proliferation in most tumor cells even under the condition of sufficient oxygen. This metabolic pattern can lead to a large accumulation of lactic acid and intracellular acidification, which can affect the growth of tumor cells and lead to cell death. Proton-coupled monocarboxylate transporters (MCTs) belong to the SLC16A gene family, which consists of 14 members. MCT1-4 promotes the passive transport of monocarboxylate (e.g., lactate, pyruvate, and ketone bodies) and proton transport across membranes. MCT1-4-mediated lactate shuttling between glycolytic tumor cells or cancer-associated fibroblasts and oxidative tumor cells plays an important role in the metabolic reprogramming of energy, lipids, and amino acids and maintains the survival of tumor cells. In addition, MCT-mediated lactate signaling can promote tumor angiogenesis, immune suppression and multidrug resistance, migration and metastasis, and ferroptosis resistance and autophagy, which is conducive to the development of tumor cells and avoid death. Although there are certain challenges, the study of targeted drugs against these transporters shows great promise and may form new anticancer treatment options.

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Overexpression of monocarboxylate transporter 4 promotes the migration and invasion of non‑carcinogenic L929 fibroblast cells

Cited by 4 publications

References 36 publications

MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells

MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells

Monocarboxylate transporter 4 promotes the migration of non‑cancerous L929 fibroblast cells by activating the IGF1/IGF1R/PIK3R3/SGK1 axis

Proton-coupled monocarboxylate transporters in cancer: From metabolic crosstalk, immunosuppression and anti-apoptosis to clinical applications

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