Article (Scientific journals)
rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
Posada, IMD; Lectez, B; Sharma, M et al.
2017In Oncotarget, Vol. 8 ((No. 27)), p. 44550-44566
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Abstract :
[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
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
External co-authors :
yes
Language :
English
Title :
rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
Publication date :
04 July 2017
Journal title :
Oncotarget
eISSN :
1949-2553
Publisher :
Impact Journals, Albany, United States - New York
Volume :
Vol. 8
Issue :
(No. 27)
Pages :
pp: 44550-44566
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 01 February 2018

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