| Reference : rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependen... |
| Scientific journals : Article | |||
| Life sciences : Biochemistry, biophysics & molecular biology | |||
| http://hdl.handle.net/10993/34348 | |||
| rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner | |
| English | |
| Posada, IMD [] | |
| Lectez, B [] | |
| Sharma, M [] | |
| Oetken-Lindholm, C [] | |
| Yetukuri, L [] | |
| Zhou, Y [] | |
| Aittokallio, T [] | |
Abankwa, Daniel  [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >] | |
| 4-Jul-2017 | |
| Oncotarget | |
| Impact Journals | |
| Vol. 8 | |
| (No. 27) | |
| pp: 44550-44566 | |
| Yes | |
| International | |
| 1949-2553 | |
| Albany | |
| NY | |
| [en] 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. | |
| Researchers | |
| http://hdl.handle.net/10993/34348 |
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