A1 Refereed original research article in a scientific journal
Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
Authors: Itziar M.D. Posada, Benoit Lectez, Mukund Sharma, Christina Oetken-Lindholm, Laxman Yetukuri, Yong Zhou, Tero Aittokallio, Daniel Abankwa
Publisher: IMPACT JOURNALS LLC
Publication year: 2017
Journal: Oncotarget
Journal name in source: ONCOTARGET
Journal acronym: ONCOTARGET
Volume: 8
Issue: 27
First page : 44550
Last page: 44566
Number of pages: 17
ISSN: 1949-2553
DOI: https://doi.org/10.18632/oncotarget.17819
Web address : https://www.ncbi.nlm.nih.gov/pubmed/28562352
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/24976230
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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