| Title: |
Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner |
| Authors: |
Posada, Itziar M. D.; Lectez, Benoit; Sharma, Mukund; Oetken-Lindholm, Christina; Yetukuri, Laxman; Zhou, Yong; Aittokallio, Tero; Abankwa, Daniel |
| Contributors: |
Institute for Molecular Medicine Finland; University of Helsinki; Tero Aittokallio / Principal Investigator; Bioinformatics |
| Publisher Information: |
Impact Journals LLC |
| Publication Year: |
2017 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
mTORC1; Ras; rapamycin; galectin; cancer stem cells; K-RAS; MEMBRANE ORIENTATION; MTOR INHIBITORS; PROTEINS; TARGET; MODEL; HRAS; NANOCLUSTERS; METASTASIS; ACTIVATION; Cancers |
| Description: |
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 reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISBN: |
978-85-02-18429-9; 85-02-18429-6 |
| Relation: |
This work was supported by the Academy of Finland grants (#292611) to TA and (#252381, 256440, 281497), the Sigrid Juselius Foundation, and the Jane and Aatos Erkko Foundation grants to DA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; https://hdl.handle.net/10138/214063; 85021842962; 000405498000078 |
| Availability: |
https://hdl.handle.net/10138/214063 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.5A71447D |
| Database: |
BASE |