Metformin Administration to Glucose-restricted Cells Attenuates PKA Signaling in S. cerevisiae

Abstract

Recent research in cancer treatment points to metformin, a drug for type 2 diabetes, as a potential anti-cancer therapeutic, as well as carbon limitation as a dietary measure. A new study, investigating effects of metformin treatment on colorectal cancer cells, pointed to the fact that response to metformin treatment depended on extracellular glucose concentration. That is why in the current study, effects of both carbon limitation and metformin treatment are explored via transcriptomics analyses. It is demonstrated that cells grown in glucose-limited and metformin treated medium had the highest variance according to transcriptional profiles, compared to individual treatments. Metformin administration, when combined with glucose restriction, downregulates proliferative pathways such as transcription initiation and ribosome biogenesis while upregulates energy derivation and autophagic mechanisms. Enrichment analyses point to an attenuated cAMP-PKA signaling pathway in the cells grown in combined treatment medium. It is proposed that combined treatment exerts its beneficial effect on this pathway, since cAMP-PKA signaling may be a potential target for pharmacological treatment of tumors.

Keywords

• S. cerevisiae
• metformin
• systems biology
• glucose restriction
• transcriptomics
• cancer

Glikozu Kısıtlı Hücrelere Uygulanan Metformin Tedavisi ile S. cerevisiae'de PKA Yolağının Baskılanması

Abstract

Kanser tedavisindeki son araştırmalar, tip 2 diyabet tedavisi için kullanılan metforminin potansiyel bir kanser önleyici terapötik olduğunu ve ayrıca bir diyet önlemi olarak karbon sınırlamasının önemini işaret etmektedir. Metformin tedavisinin kolorektal kanser hücreleri üzerindeki etkilerini araştıran yeni bir çalışma, metformin tedavisine verilen yanıtın hücre dışı glikoz konsantrasyonuna bağlı olduğu gerçeğini ortaya koymuştur. Bu nedenle bu çalışmada hem karbon sınırlamasının hem de metformin tedavisinin etkileri transkriptomik analizlerle araştırılmıştır. Glikoz-sınırlı ve metformin ile tedavi görmüş ortamda büyütülen hücrelerin, bireysel tedavilere kıyasla transkripsiyonel profillere göre en yüksek varyansa sahip olduğu gösterilmiştir. Metformin tedavisi, glikoz kısıtlaması ile birleştirildiğinde, transkripsiyon başlangıcı ve ribozom biyogenezi gibi proliferatif yolakları baskılarken, enerji ortaya çıkışı ve otofajik mekanizmaları tetiklemiştir. Gen ontolojisi zenginleştirme analizleri, kombine tedavi ortamında büyütülen hücrelerde zayıflamış bir cAMP-PKA sinyal yolağına işaret etmektedir. cAMP-PKA sinyal yolağı, tümörlerin farmakolojik tedavisi için potansiyel bir hedef olabileceğinden, kombine tedavinin yararlı etkisini bu yolak üzerinden gösterdiği düşünülmektedir.

Keywords

• system biyolojisi
• S. cerevisiae
• metformin
• glikoz kısıtlaması
• kanser
• transkriptom analizi

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