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

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http://hdl.handle.net/10138/214063

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Posada , I M D , Lectez , B , Sharma , M , Oetken-Lindholm , C , Yetukuri , L , Zhou , Y , Aittokallio , T & Abankwa , D 2017 , ' Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner ' Oncotarget , vol 8 , no. 27 , pp. 44550-44566 . DOI: 10.18632/oncotarget.17819

Title: Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
Author: Posada, Itziar M. D.; Lectez, Benoit; Sharma, Mukund; Oetken-Lindholm, Christina; Yetukuri, Laxman; Zhou, Yong; Aittokallio, Tero; Abankwa, Daniel
Contributor: University of Helsinki, Institute for Molecular Medicine Finland (FIMM)
University of Helsinki, Institute for Molecular Medicine Finland (FIMM)
Belongs to series: Oncotarget
ISSN: 1949-2553
Abstract: 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.
Peer review status: Peer reviewed
URI: http://hdl.handle.net/10138/214063
Date: 2017-07-04
Subject: mTORC1
Ras
rapamycin
galectin
cancer stem cells
K-RAS
MEMBRANE ORIENTATION
MTOR INHIBITORS
PROTEINS
TARGET
MODEL
HRAS
NANOCLUSTERS
METASTASIS
ACTIVATION
3122 Cancers
Rights: CC BY 3.0


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