title: Tyrosine kinase inhibitor SU11274 increased tumorigenicity and enriched for melanoma-initiating cells by bioenergetic modulation.
abstract: Small molecule inhibitor of tyrosine kinase activity, compound SU11274, was reported to have antitumorigenic and antimetastatic effect in melanoma. In this study, we evaluated, whether similar effect could be achieved also in other melanoma cells including highly tumorigenic and hypermetastatic variant.
  
  
  
  The effect of SU11274 was evaluated in adherent and non-adherent melanosphere cultures of human melanoma cells M14, M4Beu, A375 and EGFP-A375/Rel3. Tumorigenicity of SU11274-treated cells was tested by limiting dilution assay in xenograft model in vivo.
  
  
  
  Here we show that SU11274 enriched for melanoma-initiating cells in vivo. SU11274 substantially decreased number of cells in adherent and spheroid cultures, but increased their tumorigenic potential as determined by higher frequency of tumor-initiating cells in vivo. SU11274 treatment was not associated with any significant alteration in the expression of stem cell markers, but the inhibitor stimulated higher level of pluripotent markers. SU11274-treated melanoma cells exhibited higher ATP content and lactate release indicative of increased glycolysis. Our data suggest that the SU11274 altered bioenergetic state of the cells. Indeed, pharmacological intervention with a glycolytic inhibitor dichloroacetate significantly reduced SU11274-promoted increase in melanoma-initiating cells and decreased their tumorigenicity.
  
  
  
  Our data suggest critical role of glycolysis regulation in melanoma-initiating cells. Moreover, these data unravel substantial plasticity of melanoma cells and their adoptive mechanisms, which result in ambivalent response to therapeutic targeting.
authors.affiliation: Laboratory of Molecular Oncology, Cancer Research Institute of Biomedical Research Centre, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, 845 05, Slovakia. lucia.kucerova@savba.sk.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kucerova
authors.affiliation: Laboratory of Molecular Oncology, Cancer Research Institute of Biomedical Research Centre, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, 845 05, Slovakia.
authors.forename: Lucia
authors.initials: L
authors.lastname: Demkova
authors.affiliation: Laboratory of Molecular Oncology, Cancer Research Institute of Biomedical Research Centre, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, 845 05, Slovakia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Skolekova
authors.affiliation: Laboratory of Molecular Oncology, Cancer Research Institute of Biomedical Research Centre, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, 845 05, Slovakia.
authors.forename: Roman
authors.initials: R
authors.lastname: Bohovic
authors.affiliation: Laboratory of Molecular Oncology, Cancer Research Institute of Biomedical Research Centre, Slovak Academy of Sciences, Dubravska cesta 9, Bratislava, 845 05, Slovakia.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Matuskova
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides
keywords: Bioenergetic modulation; Human melanoma; Melanoma-initiating cells; SU11274; c-Met receptor