PFKFB3 Küçük Molekül İnhibitörü KAN0438757'nin Glioblastoma Hücre Hatlarında Hücre Migrasyonu ve N-kadherin Proteininin Ekspresyon Düzeyi Üzerine Etkilerinin Araştırılması

Year 2024, , 47 - 53, 26.03.2024

Seher Saruhan , Deniz Özdemir , Remziye Safa , Can Ali Agca

https://doi.org/10.46810/tdfd.1385118

Abstract

Tümör hücrelerinde enerji metabolizmasının yeniden programlanmasının, malign özelliklerle ilişkili epitelyal-mezenkimal geçiş (EMT) programının desteklenmesinde önemli bir rol oynadığı bilinmektedir. Enerji metabolizmasında görev alan PFKFB3 (6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase 3), glioblastoma dahil olmak üzere çoklu tümör tipi ilerlemesinde rol oynayan önemli bir glikolitik aktivatördür. PFKFB3, EMT ile ilişkili proteinlerin ekspresyonunu modüle ederek tümör hücrelerinde EMT programını etkileyebilmektedir. EMT sırasında glioblastoma hücreleri, artan hücre hareketliliği, istilacılık ve tedaviye direnç ile ilişkili bir mezenkimal fenotip kazanmaktadır. Glioblastoma hücrelerinde PFKFB3'ün inhibisyonu, EMT'yi hedeflemek ve kanser ilerlemesini engellemek için potansiyel bir terapötik strateji olarak görülmektedir. PFKFB3 inhibitörleri, PFKFB3'ün aktivitesini bloke edebilen ve dolayısıyla kanser hücrelerinde glikoliz sürecini inhibe edebilen bileşiklerdir. KAN0438757, PFKFB3'ün yeni ve seçici bir inhibitörüdür. KAN0438757'nin hem in vitro hem de in vivo olarak çeşitli kanser modellerinde anti-tümör etkilerine sahip olduğu gösterilmiştir. Yeni inhibitörün glioblastoma kanseri hücre hatları U373 ve U251'de hücrelerin canlılığı, hücre göçü ve hücre ölümü üzerindeki etkisi, WST-1 hücre canlılığı, AO/EtBr boyama western blotlama ve yara iyileştirme testleri ile araştırıldı. Elde ettiğimiz sonuçlarda, Glioblastoma hücrelerinde, KAN0438757 tedavisinden sonra hücre canlılığının azaldığı ve doza bağlı apoptotik morfolojik değişiklikler görüldü. Ayrıca EMT ilişkili protein N-cadherin proteininin düzeyinin azaldığı ve hücre göçününde baskılandığını gözlemledik. Sonuç olarak, KAN0438757'nin glioblastomada, EMT programını tersine çevirerek ve kanser hücrelerinin apoptotik morfolojik değişikliklere yol açarak anti-tümör etkilerine sahip olabileceğini düşündürmektedir.

Keywords

KAN0438757, PFKFB3, Glioblastoma, Hücre göçü

Investigation of the Effects of PFKFB3 Small Molecule Inhibitor KAN0438757 on Cell Migration and Expression Level of N-cadherin Protein in Glioblastoma Cell Lines

Abstract

PFKFB3 (6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase 3) is a enzyme involved in glycolysis, the process by which cells convert glucose into energy. PFKFB3 is known to be overexpressed in many types of cancer, including glioblastoma, a highly aggressive brain tumour. The epithelial-mesenchymal transition (EMT) is a biological mechanism linked to cancer growth and enhanced invasion and metastasis. Inhibition of PFKFB3 in glioblastoma cells is seen as a potential therapeutic strategy to target EMT and inhibit cancer progression. Various small molecule PFKFB3 inhibitors have been created and tested in preclinical trials. The purpose of this study is to look into the possible effect of KAN0438757, a very efficient PFKB3 inhibitor, on glioblastoma cells. KAN0438757's impact on viability of cells, cell migration and cell death in glioblastoma cancer cell lines U373 and U251 were investigated by WST-1 Cell viability, AO/EtBr staining western blotting and wound healing-cell migration assays. Glioblastoma cells showed decreased cell viability and dose-dependent apoptotic morphological changes after KAN0438757 treatment. In addition, it was determined that N-cadherin protein level decreased and cell migration was suppressed. In conclusion, KAN0438757, a PFKFB3 inhibitor, can be considered as a valid approach to target cell death and EMT in glioblastoma cancer cell lines.

Keywords

KAN0438757, PFKFB3, Glioblastoma, Migration

Supporting Institution

TÜBİTAK

Thanks

This research was funded by TÜBİTAK

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