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

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)

Interna författare/redaktörer

Publikationens författare: Posada IMD, Lectez B, Sharma M, Oetken-Lindholm C, Yetukuri L, Zhou Y, Aittokallio T, Abankwa D
Publiceringsår: 2017
Tidskrift: Oncotarget
Tidskriftsakronym: ONCOTARGET
Volym: 8
Artikelns första sida, sidnummer: 44550
Artikelns sista sida, sidnummer: 44566
Antal sidor: 17
ISSN: 1949-2553


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.


cancer stem cells, galectin, mTORC1, rapamycin, Ras

Senast uppdaterad 2019-20-06 vid 06:19