A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner
Tekijät: Itziar M.D. Posada, Benoit Lectez, Mukund Sharma, Christina Oetken-Lindholm, Laxman Yetukuri, Yong Zhou, Tero Aittokallio, Daniel Abankwa
Kustantaja: IMPACT JOURNALS LLC
Julkaisuvuosi: 2017
Journal: Oncotarget
Tietokannassa oleva lehden nimi: ONCOTARGET
Lehden akronyymi: ONCOTARGET
Vuosikerta: 8
Numero: 27
Aloitussivu: 44550
Lopetussivu: 44566
Sivujen määrä: 17
ISSN: 1949-2553
DOI: https://doi.org/10.18632/oncotarget.17819
Verkko-osoite: https://www.ncbi.nlm.nih.gov/pubmed/28562352
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/24976230
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
