Cancer stem cell drugs target K-ras signaling in a stemness context

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http://hdl.handle.net/10138/169279

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Najumudeen , A K , Jaiswal , A , Lectez , B , Oetken-Lindholm , C , Guzman , C , Siljamaki , E , Posada , I M D , Lacey , E , Aittokallio , T & Abankwa , D 2016 , ' Cancer stem cell drugs target K-ras signaling in a stemness context ' , Oncogene , vol. 35 , no. 40 , pp. 5248-5262 . https://doi.org/10.1038/onc.2016.59

Title: Cancer stem cell drugs target K-ras signaling in a stemness context
Author: Najumudeen, A. K.; Jaiswal, A.; Lectez, B.; Oetken-Lindholm, C.; Guzman, C.; Siljamaki, E.; Posada, I. M. D.; Lacey, E.; Aittokallio, T.; Abankwa, D.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2016-10-06
Language: eng
Number of pages: 15
Belongs to series: Oncogene
ISSN: 0950-9232
URI: http://hdl.handle.net/10138/169279
Abstract: Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.
Subject: GENE-EXPRESSION
MEMBRANE ORIENTATION
PLASMA-MEMBRANE
SALINOMYCIN
PROTEINS
NANOCLUSTERS
RESISTANCE
CAVEOLIN-1
PHOSPHATIDYLSERINE
IDENTIFICATION
3111 Biomedicine
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