title: The MCT4 Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer.
abstract: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling-directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer.
  
  
  
  A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice.
  
  
  
  Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity.
  
  
  
  MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721-33. ©2016 AACR.
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Stephen Yiu Chuen
authors.initials: SY
authors.lastname: Choi
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wu
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Lin
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gout
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia, Canada. Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada. ywang@bccrc.ca.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D008297:Male; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000235:genetics*; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D016376:Oligonucleotides, Antisense; C406962:SLC16A4 protein, human; D005947:Glucose