Targeting lactate transport suppresses<i>in vivo</i>breast tumour growth

Morais-Santos, Filipa; Granja, Sara; Miranda-Gonçalves, Vera; Moreira, António H. J.; Queirós, Sandro; Vilaça, João L.; Schmitt, Fernando; Longatto‐Filho, Adhemar; Paredes, Joana; Baltazar, Fátima; Pinheiro, Céline

doi:10.18632/oncotarget.3910

Cited by 96 publications

(85 citation statements)

References 43 publications

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“…Downregulation of MCT1 or MCT4 was performed with siRNA (siRNA for MCT1, s580, Ambion; scramble siRNA, 4390843, Ambion, siRNA for MCT4, S17417) using lipofectamine as a transfection reagent, according to the manufacturer's instructions [49]. …”

Section: Methodsmentioning

confidence: 99%

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

et al. 2016

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BackgroundGlioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular.MethodsExpression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions.ResultsHypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX.ConclusionHypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.

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Section: Methodsmentioning

confidence: 99%

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

et al. 2016

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“…The re mark able de pen dency for sur vival of hy poxic/ gly colytic can cer cells on the meta bolic pref er ences of nor moxic/ ox ida tive ones mo ti vated the de vel op ment of strate gies aimed to in ter fere with the ex change of lac tate. Ther a peu tic in ter ven tions could be aimed at in hibit ing MCT4 in hy poxic can cer cell com part ments [86], in hibit ing MCT1 [5,[87][88][89] and lac tate up take [90,91] in oxy genated/ ox ida tive can cer cells, in hibit ing LDHB [76,92] or, pos si bly, in hibit ing the mi to chon dr ial pyru vate car rier in ox ida tive can cer cells [93]. In our opin ion, fu ture ther a peu tic de vel op ments should aim at tar get ing the ox ida tive path way of lac tate in can cer cells that re side close to drug de liv er ing blood ves sels.…”

Section: Metabolic Cooperation In Cancermentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

162

139

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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“…[50][51][52] Specificity of the antibodies was previously validated by siRNA followed by Western-blot. 53,54 Negative controls were performed by the use of appropriate serum controls for the primary antibodies (Dako, #N1698 and #N1699). Colon carcinoma tissue was used as positive control for MCT1 and MCT4, head and neck squamous cell carcinoma was used for GLUT1, and normal stomach was used for CAIX.…”

Section: Immunohistochemistrymentioning

confidence: 99%

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4

et al. 2016

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BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.

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Targeting lactate transport suppressesin vivobreast tumour growth

Cited by 96 publications

References 43 publications

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas

Cancer metabolism in space and time: Beyond the Warburg effect

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4

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