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
rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
Posada, IMD []
Lectez, B []
Sharma, M []
Oetken-Lindholm, C []
Yetukuri, L []
Zhou, Y []
Aittokallio, T []
Abankwa, Daniel mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit >]
Impact Journals
Vol. 8
(No. 27)
pp: 44550-44566
[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.

File(s) associated to this reference

Fulltext file(s):

Open access
oncotarget-08-44550_Daniel Abankwa.pdfPublisher postprint7.89 MBView/Open

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.