Interaction of monocarboxylate transporter 4 with β<sub>1</sub>-integrin and its role in cell migration

Gallagher, Shannon M.; Castorino, John J.; Philp, Nancy J.

doi:10.1152/ajpcell.00430.2008

Cited by 69 publications

(64 citation statements)

References 58 publications

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“…In this context, it is interesting that the Basigin/MCT4 complex has been found to associate with integrin β1 and localize at the leading edge of migrating cells, an area very active for invasive growth and also very demanding in metabolic energy (44). More importantly Philp et al (45) reported that silencing MCT4 but not MCT1 in retinal pigment epithelial cells slowed down their migration, a process highly controlled by pH.…”

Section: Discussionmentioning

confidence: 99%

CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

Floch

Chiche

Marchiq

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

375

325

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Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H + /lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res − ) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res − cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, highlighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H + symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin high cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy.

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Section: Discussionmentioning

confidence: 99%

CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

Floch

Chiche

Marchiq

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

375

325

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“…Interestingly, heterocomplexes of CD147 with MCT4 (primarily involved in monocarboxylate export) 4,5 have been previously reported to colocalize with b1-integrin at the leading edge lamellipodia of migrating cells, 45 supporting a role of MCTs in migration. Here, we documented that MCT1-CD147 complexes that accumulate in glucose-deprived cells are present among other locations in such protrusions ( Figure 5 and Supplementary Figure 5) and regulate the migratory phenotype ( Figure 6).…”

Section: Discussionmentioning

confidence: 85%

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

et al. 2013

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The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins. In this study, we found that glucose deprivation dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this posttranslational induction could be recapitulated using glycolysis inhibition, hypoxia, oxidative phosphorylation (OXPHOS) inhibitor rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes accumulated, including in cell protrusions of the plasma membrane. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration increased in cells overexpressing MCT1 and CD147, but it was inhibited in glucose-starved cells provided with an alternative oxidative fuel, treated with an antioxidant, lacking MCT1 expression, or submitted to pharmacological MCT1 inhibition. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer.

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“…Additionally, silencing of MCT4 results in decreased cancer cell migration (Gallagher et al 2007), by mechanisms that also involve interaction of MCT4 with β 1 -integrin (Gallagher et al 2009). In opposition, another study showed that silencing of MCT1 or MCT4 inhibited cancer cell invasion, but did not influence cell migration (Izumi et al 2011).…”

Section: Mcts As Therapeutic Targets In Cancermentioning

confidence: 99%

Role of monocarboxylate transporters in human cancers: state of the art

Pinheiro

Longatto‐Filho

Azevedo-Silva

et al. 2012

J Bioenerg Biomembr

330

295

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Monocarboxylate transporters (MCTs) belong to the SLC16 gene family, presently composed by 14 members. MCT1-MCT4 are proton symporters, which mediate the transmembrane transport of pyruvate, lactate and ketone bodies. The role of MCTs in cell homeostasis has been characterized in detail in normal tissues, however, their role in cancer is still far from understood. Most solid tumors are known to rely on glycolysis for energy production and this activity leads to production of important amounts of lactate, which are exported into the extracellular milieu, contributing to the acidic microenvironment. In this context, MCTs will play a dual role in the maintenance of the hyper-glycolytic acid-resistant phenotype of cancer, allowing the maintenance of the high glycolytic rates by performing lactate efflux, and pH regulation by the co-transport of protons. Thus, they constitute attractive targets for cancer therapy, which have been little explored. Here we review the literature on the role of MCTs in solid tumors in different locations, such as colon, central nervous system, breast, lung, gynecologic tract, prostate, stomach, however, there are many conflicting results and in most cases there are no functional studies showing the dependence of the tumors on MCT expression and activity. Additional studies on MCT expression in other tumor types, confirmation of the results already published as well as additional functional studies are needed to deeply understand the role of MCTs in cancer maintenance and aggressiveness.

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Interaction of monocarboxylate transporter 4 with β₁-integrin and its role in cell migration

Cited by 69 publications

References 58 publications

CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

Role of monocarboxylate transporters in human cancers: state of the art

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Interaction of monocarboxylate transporter 4 with β1-integrin and its role in cell migration

Cited by 69 publications

References 58 publications

CD147 subunit of lactate/H+symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

CD147 subunit of lactate/H+symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

Role of monocarboxylate transporters in human cancers: state of the art

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Interaction of monocarboxylate transporter 4 with β₁-integrin and its role in cell migration

CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors

CD147 subunit of lactate/H⁺symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors