Tyrosine kinase inhibitor SU11274 increased tumorigenicity and enriched for melanoma-initiating cells by bioenergetic modulation

BMC Cancer

Research Article

Miroslava Matuskova¹  Svetlana Skolekova¹  Lucia Kucerova¹  Lucia Demkova¹  Roman Bohovic¹ 

[1] Laboratory of Molecular Oncology, Cancer Research Institute of Biomedical Research Centre, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia;

关键词: Human melanoma;    Melanoma-initiating cells;    c-Met receptor;    SU11274;    Bioenergetic modulation;   

DOI  :  10.1186/s12885-016-2341-y

 received in 2015-09-10, accepted in 2016-05-08,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundSmall 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.MethodsThe 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.ResultsHere 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© Kucerova et al. 2016