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

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

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

Benoit Lectez
Christina Oetken-Lindholm
Yong Zhou
Itziar M.D. Posada
Mukund Sharma
Tero Aittokallio
Daniel Abankwa
Laxman Yetukuri
Katso/Avaa
Attribution 3.0 Unported (CC BY 3.0) (7.701Mb)
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IMPACT JOURNALS LLC
doi:10.18632/oncotarget.17819
URI
https://www.ncbi.nlm.nih.gov/pubmed/28562352
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042716956
Tiivistelmä
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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