title: Monocarboxylate transport inhibition potentiates the cytotoxic effect of 5-fluorouracil in colorectal cancer cells.
abstract: Cancer cells rely mostly on glycolysis to meet their energetic demands, producing large amounts of lactate that are extruded to the tumour microenvironment by monocarboxylate transporters (MCTs). The role of MCTs in the survival of colorectal cancer (CRC) cells is scarce and poorly understood. In this study, we aimed to better understand this issue and exploit these transporters as novel therapeutic targets alone or in combination with the CRC classical chemotherapeutic drug 5-Fluorouracil. For that purpose, we characterized the effects of MCT activity inhibition in normal and CRC derived cell lines and assessed the effect of MCT inhibition in combination with 5-FU. Here, we demonstrated that MCT inhibition using CHC (α-cyano-4-hydroxycinnamic acid), DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and quercetin decreased cell viability, disrupted the glycolytic phenotype, inhibited proliferation and enhanced cell death in CRC cells. These results were confirmed by specific inhibition of MCT1/4 by RNA interference. Notably, we showed that 5-FU cytotoxicity was potentiated by lactate transport inhibition in CRC cells, either by activity inhibition or expression silencing. These findings provide novel evidence for the pivotal role of MCTs in CRC maintenance and survival, as well as for the use of these transporters as potential new therapeutic targets in combination with CRC conventional therapy.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Amorim
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil; Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, Sao Paulo, Brazil.
authors.forename: Céline
authors.initials: C
authors.lastname: Pinheiro
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Vera
authors.initials: V
authors.lastname: Miranda-Gonçalves
authors.affiliation: Centre of Molecular and Environmental Biology (CBMA)/Department of Biology, University of Minho, Braga, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Pereira
authors.affiliation: INCELL Corporation, San Antonio, TX, USA.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: Centre of Molecular and Environmental Biology (CBMA)/Department of Biology, University of Minho, Braga, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Preto
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: fbaltazar@ecsaude.uminho.pt.
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D049990:Membrane Transport Modulators / Q000494:pharmacology; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D019344:Lactic Acid; D049990:Membrane Transport Modulators; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human
keywords: 5-Fluorouracil; Colorectal cancer; Glycolytic metabolism; Lactate transport; Monocarboxylate transporters