期刊
MOLECULAR CANCER THERAPEUTICS
卷 13, 期 11, 页码 2537-2546出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-14-0256
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资金
- Academy of Finland [251307]
- Johns Hopkins University start-up funds
- NIH [P30 CA006973, P50 CA058236, 1R01 CA172069]
- Biomedicum Helsinki Foundation
- Cancer Society Finland
- Finnish Cultural Foundation
- Academy of Finland (AKA) [251307, 251307] Funding Source: Academy of Finland (AKA)
Activation of the p53 pathway has been considered a therapeutic strategy to target cancers. We have previously identified several p53-activating small molecules in a cell-based screen. Two of the compounds activated p53 by causing DNA damage, but this modality was absent in the other four. We recently showed that one of these, BMH-21, inhibits RNA polymerase I (Pol I) transcription, causes the degradation of Pol I catalytic subunit RPA194, and has potent anticancer activity. We show here that three remaining compounds in this screen, BMH-9, BMH-22, and BMH-23, cause reorganization of nucleolar marker proteins consistent with segregation of the nucleolus, a hallmark of Pol I transcription stress. Further, the compounds destabilize RPA194 in a proteasome-dependent manner and inhibit nascent rRNA synthesis and expression of the 45S rRNA precursor. BMH-9 and BMH-22-mediated nucleolar stress was detected in ex vivo-cultured human prostate tissues indicating good tissue bioactivity. Testing of closely related analogues showed that their activities were chemically constrained. Viability screen for BMH-9, BMH-22, and BMH-23 in the NCI60 cancer cell lines showed potent anticancer activity across many tumor types. Finally, we show that the Pol I transcription stress by BMH-9, BMH-22, and BMH-23 is independent of p53 function. These results highlight the dominant impact of Pol I transcription stress on p53 pathway activation and bring forward chemically novel lead molecules for Pol I inhibition, and, potentially, cancer targeting. (C) 2014 AACR.
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