Functional screening identifies <scp>MCT4</scp> as a key regulator of breast cancer cell metabolism and survival

Baenke, Franziska; Dubuis, Sébastien; Brault, C.; Weigelt, Britta; Dankworth, Beatrice; Griffiths, Beatrice; Jiang, Ming; Mackay, Alan; Saunders, Becky; Spencer‐Dene, Bradley; Ros, Susana; Stamp, Gordon; Reis‐Filho, Jorge S.; Howell, Michael; Zamboni, Nicola; Schulze, Almut

doi:10.1002/path.4562

Cited by 84 publications

(78 citation statements)

References 49 publications

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“…The MCTs can also sensitize cells to radiation therapy [74, 75]. As a result, MCTs have been considered a therapeutic target, either alone or in combination with other therapies [61, 69, 70, 74, 76-79]. However, in the current study, we show that expression of MCT1 and MCT4 is significantly reduced in mutant IDH1 gliomas.…”

Section: Discussioncontrasting

confidence: 54%

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Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters

et al. 2016

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Mutations in isocitrate dehydrogenase 1 (IDH1) are characteristic of low-grade gliomas. We recently showed that mutant IDH1 cells reprogram cellular metabolism by down-regulating pyruvate dehydrogenase (PDH) activity. Reduced pyruvate metabolism via PDH could lead to increased pyruvate conversion to lactate. The goal of this study was therefore to investigate the impact of the IDH1 mutation on the pyruvate-to-lactate flux. We used 13C magnetic resonance spectroscopy and compared the conversion of hyperpolarized [1-13C]-pyruvate to [1-13C]-lactate in immortalized normal human astrocytes expressing mutant or wild-type IDH1 (NHAIDHmut and NHAIDHwt). Our results indicate that hyperpolarized lactate production is reduced in NHAIDHmut cells compared to NHAIDHwt. This reduction was associated with lower expression of the monocarboxylate transporters MCT1 and MCT4 in NHAIDHmut cells. Furthermore, hyperpolarized lactate production was comparable in lysates of NHAIDHmut and NHAIDHwt cells, wherein MCTs do not impact hyperpolarized pyruvate delivery and lactate production. Collectively, our findings indicated that lower MCT expression was a key contributor to lower hyperpolarized lactate production in NHAIDHmut cells. The SLC16A3 (MCT4) promoter but not SLC16A1 (MCT1) promoter was hypermethylated in NHAIDHmut cells, pointing to possibly different mechanisms mediating reduced MCT expression. Finally analysis of low-grade glioma patient biopsy data from The Cancer Genome Atlas revealed that MCT1 and MCT4 expression was significantly reduced in mutant IDH1 tumors compared to wild-type. Taken together, our study shows that reduced MCT expression is part of the metabolic reprogramming of mutant IDH1 gliomas. This finding could impact treatment and has important implications for metabolic imaging of mutant IDH1 gliomas.

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Section: Discussioncontrasting

confidence: 54%

“…Elevated expression of the MCTs has been observed in highly glycolytic tumors and has been associated with poor outcome [11, 69, 70]. Additionally, the MCTs have been shown to impact the effects of chemotherapeutic agents such as 3-bromopyruvate and dichloroacetate by modulating their delivery to the cell [71-73].…”

Section: Discussionmentioning

confidence: 99%

Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters

et al. 2016

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“…33,34 While an increase in pH i is sufficient to induce dysplasia at least under some conditions, 35 it is also well accepted that at least NHE1 plays additional roles, including scaffolding of signaling components. While the relative roles of the transporters in pH i homeostasis may differ in vitro and in vivo, we favor the interpretation that MCT4 KD in the MDA-MB-231 cells, which lack MCT1, compromises lactate efflux so substantially that glycolysis is essentially abrogated, reducing metabolic acid production and thus allowing pH i to be maintained by other net acid extruders (NHE1 and NBCn1).…”

Section: Discussionmentioning

confidence: 99%

The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms

Andersen

Samsøe-Petersen

Oernbo

et al. 2018

Intl Journal of Cancer

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High metabolic and proliferative rates in cancer cells lead to production of large amounts of H and CO , and as a result, net acid extruding transporters are essential for the function and survival of cancer cells. We assessed protein expression of the Na /H exchanger NHE1, the Na - HCO3- cotransporter NBCn1, and the lactate-H cotransporters MCT1 and -4 by immunohistochemical analysis of a large cohort of breast cancer samples. We found robust expression of these transporters in 20, 10, 4 and 11% of samples, respectively. NHE1 and NBCn1 expression both correlated positively with progesterone receptor status, NHE1 correlated negatively and NBCn1 positively with HER2 status, whereas MCT4 expression correlated with lymph node status. Stable shRNA-mediated knockdown (KD) of either NHE1 or NBCn1 in the MDA-MB-231 triple-negative breast cancer (TNBC) cell line significantly reduced steady-state intracellular pH (pH ) and capacity for pH recovery after an acid load. Importantly, KD of any of the three transporters reduced in vivo primary tumor growth of MDA-MB-231 xenografts. However, whereas KD of NBCn1 or MCT4 increased tumor-free survival and decreased in vitro proliferation rate and colony growth in soft agar, KD of NHE1 did not have these effects. Moreover, only MCT4 KD reduced Akt kinase activity, PARP and CD147 expression and cell motility. This work reveals that different types of net acid extruding transporters, NHE1, NBCn1 and MCT4, are frequently expressed in patient mammary tumor tissue and demonstrates for the first time that they promote growth of TNBC human mammary tumors in vivo via distinct but overlapping mechanisms.

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“…MCT4 expression in cancers such as HNSCC, breast cancer, melanoma, and hepatocellular carcinoma has been associated with a poor prognosis (5, 26–28). In patient tumors, MCT4 has been detected in cancer cells, cancer associated fibroblasts (CAFs) as well as tumor associated macrophages (TAMs) where it supports tumor growth (17), angiogenesis (29), and metastasis (30) (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporter 4 (MCT4) Knockout Mice Have Attenuated 4NQO Induced Carcinogenesis; A Role for MCT4 in Driving Oral Squamous Cell Cancer

et al. 2018

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Head and neck squamous cell carcinoma (HNSCC) is the 6th most common human cancer and affects approximately 50,000 new patients every year in the US. The major risk factors for HNSCC are tobacco and alcohol consumption as well as oncogenic HPV infections. Despite advances in therapy, the overall survival rate for all-comers is only 50%. Understanding the biology of HNSCC is crucial to identifying new biomarkers, implementing early diagnostic approaches and developing novel therapies. As in several other cancers, HNSCC expresses elevated levels of MCT4, a member of the SLC16 family of monocarboxylate transporters. MCT4 is a H+-linked lactate transporter which functions to facilitate lactate efflux from highly glycolytic cells. High MCT4 levels in HNSCC have been associated with poor prognosis, but the role of MCT4 in the development and progression of this cancer is still poorly understood. In this study, we used 4-nitroquinoline-1-oxide (4NQO) to induce oral cancer in MCT4−/− and wild type littermates, recapitulating the disease progression in humans. Histological analysis of mouse tongues after 23 weeks of 4NQO treatment showed that MCT4−/− mice developed significantly fewer and less extended invasive lesions than wild type. In mice, as in human samples, MCT4 was not expressed in normal oral mucosa but was detected in the transformed epithelium. In the 4NQO treated mice we detected MCT4 in foci of the basal layer undergoing transformation, and progressively in areas of carcinoma in situ and invasive carcinomas. Moreover, we found MCT4 positive macrophages within the tumor and in the stroma surrounding the lesions in both human samples of HNSCC and in the 4NQO treated animals. The results of our studies showed that MCT4 could be used as an early diagnostic biomarker of HNSCC. Our finding with the MCT4−/− mice suggest MCT4 is a driver of progression to oral squamous cell cancer and MCT4 inhibitors could have clinical benefits for preventing invasive HNSCC.

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Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival

Cited by 84 publications

References 49 publications

Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters

Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters

The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms

Monocarboxylate Transporter 4 (MCT4) Knockout Mice Have Attenuated 4NQO Induced Carcinogenesis; A Role for MCT4 in Driving Oral Squamous Cell Cancer

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