期刊
ONCOGENE
卷 35, 期 40, 页码 5248-5262出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.59
关键词
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资金
- Academy of Finland fellowship grant
- Sigrid Juselius Foundation
- Cancer Society of Finland
- Marie-Curie Reintegration Grant
- Jane and Aatos Erkko Foundation
- Academy of Finland [272437, 269862, 279163]
- ISB graduate school
- Integrative Life Science Doctoral Program (ILS)
- Cancer Foundation Finland sr [150062] Funding Source: researchfish
- Academy of Finland (AKA) [272437, 269862, 279163, 279163, 272437, 269862] Funding Source: Academy of Finland (AKA)
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.
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