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

: Itziar M.D. Posada, Benoit Lectez, Mukund Sharma, Christina Oetken-Lindholm, Laxman Yetukuri, Yong Zhou, Tero Aittokallio, Daniel Abankwa

Publisher: IMPACT JOURNALS LLC

: 2017

: Oncotarget

: ONCOTARGET

: 8

: 27

: 44550

: 44566

: 17

: 1949-2553

DOI: https://doi.org/10.18632/oncotarget.17819

: https://www.ncbi.nlm.nih.gov/pubmed/28562352

: 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.

17819-260217-4-PB.pdf