Oncotarget

Research Papers:

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

Itziar M.D Posada, Benoit Lectez, Mukund Sharma, Christina Oetken-Lindholm, Laxman Yetukuri, Yong Zhou, Tero Aittokallio and Daniel Abankwa _

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Oncotarget. 2017; 8:44550-44566. https://doi.org/10.18632/oncotarget.17819

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Abstract

Itziar M.D. Posada1,*, Benoit Lectez1,*, Mukund Sharma1, Christina Oetken-Lindholm1, Laxman Yetukuri1,3, Yong Zhou2, Tero Aittokallio3,4 and Daniel Abankwa1

1Turku Center for Biotechnology, Åbo Akademi University, Tykistökatu 6B, Turku, Finland

2Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America

3Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland

4Department of Mathematics and Statistics, University of Turku, Turku, Finland

*These authors have contributed equally to this work

Correspondence to:

Daniel Abankwa, email: [email protected]

Keywords: mTORC1, Ras, rapamycin, galectin, cancer stem cells

Received: January 31, 2017     Accepted: April 22, 2017     Published: May 11, 2017

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.


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