Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
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Itziar M.D. Posada1,*, Benoit Lectez1,*, Mukund Sharma1, Christina Oetken-Lindholm1, Laxman Yetukuri1,3, Yong Zhou2, Tero Aittokallio3,4 and Daniel Abankwa1
1Turku Center for Biotechnology, Åbo Akademi University, Tykistökatu 6B, Turku, Finland
2Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
3Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland
4Department of Mathematics and Statistics, University of Turku, Turku, Finland
*These authors have contributed equally to this work
Daniel Abankwa, email: [email protected]
Keywords: mTORC1, Ras, rapamycin, galectin, cancer stem cells
Received: January 31, 2017 Accepted: April 22, 2017 Published: May 11, 2017
Currently several combination treatments of mTor- and Ras-pathway inhibitors are being tested in cancer 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 to an inadvertent rapalog induced activation of tumorigenicity in Ras transformed cells. We find that rapalogs specifically increase nanoscale clustering (nanoclustering) of oncogenic H-ras but not K-ras on the plasma membrane. This increases H-ras signaling output, promotes mammosphere numbers in a H-ras-dependent manner and tumor growth in ovo. Surprisingly, also other FKBP12 binders, but not mTor-inhibitors, robustly decrease FKBP12 levels after prolonged (>2 days) exposure. This leads to an upregulation of the nanocluster scaffold galectin-1 (Gal-1), which is responsible for the rapamycin-induced increase in H-ras nanoclustering and signaling output. We provide evidence that Gal-1 promotes stemness features in tumorigenic cells. Therefore, it may be necessary to block inadvertent induction of stemness traits in H-ras transformed cells by specific Gal-1 inhibitors that abrogate its effect on H-ras nanocluster. On a more general level, our findings may add an important mechanistic explanation to the pleiotropic physiological effects that are observed with rapalogs.
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