Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner.

摘要: // Itziar M.D. Posada 1, * , Benoit Lectez Mukund Sharma 1 Christina Oetken-Lindholm Laxman Yetukuri 3 Yong Zhou 2 Tero Aittokallio 3, 4 and Daniel Abankwa Turku Center for Biotechnology, Abo Akademi University, Tykistokatu 6B, Turku, Finland Department of Integrative Biology Pharmacology, McGovern Medical School, University Texas Health Science at Houston, Texas, United States America Institute Molecular Medicine Finland, FIMM, Helsinki, Mathematics Statistics, These authors have contributed equally to this work Correspondence to: Abankwa, email: daniel.abankwa@btk.fi Keywords: mTORC1, Ras, rapamycin, galectin, cancer stem cells Received: January 31, 2017      Accepted: April 22, Published: May 11, 2017 ABSTRACT Currently several combination treatments mTor- Ras-pathway inhibitors are being tested in therapy. While multiple feedback loops render these central signaling pathways robust, they complicate drug targeting. Here, we describe a novel H-ras specific feedback, which leads an inadvertent rapalog induced activation tumorigenicity Ras transformed cells. We find that rapalogs specifically increase nanoscale clustering (nanoclustering) oncogenic but not K-ras on the plasma membrane. This increases output, promotes mammosphere numbers H-ras-dependent manner tumor growth ovo . Surprisingly, also other FKBP12 binders, mTor-inhibitors, robustly decrease levels after prolonged (>2 days) exposure. upregulation nanocluster scaffold galectin-1 (Gal-1), is responsible rapamycin-induced nanoclustering output. provide evidence Gal-1 stemness features tumorigenic Therefore, it may be necessary block induction traits by abrogate its effect nanocluster. On more general level, our findings add important mechanistic explanation pleiotropic physiological effects observed with rapalogs.