Efficacy of a small molecule inhibitor of the transcriptional cofactor PC4 in prevention and treatment of non-small cell lung cancer.

Autor: Zhang Y; AscentGene, Inc., Gaithersburg, MD, United States of America., Pavlov A; AscentGene, Inc., Gaithersburg, MD, United States of America., Malik S; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, United States of America., Chen H; AscentGene, Inc., Gaithersburg, MD, United States of America., Kim N; AscentGene, Inc., Gaithersburg, MD, United States of America., Li Z; AscentGene, Inc., Gaithersburg, MD, United States of America., Zhang X; National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America., DePamphilis ML; National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States of America., Roeder RG; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, United States of America., Ge H; AscentGene, Inc., Gaithersburg, MD, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Mar 31; Vol. 15 (3), pp. e0230670. Date of Electronic Publication: 2020 Mar 31 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0230670
Abstrakt: The human positive coactivator 4 (PC4) was originally identified as a multi-functional cofactor capable of mediating transcription activation by diverse gene- and tissue-specific activators. Recent studies suggest that PC4 might also function as a novel cancer biomarker and therapeutic target for different types of cancers. siRNA knockdown studies indicated that down-regulation of PC4 expression could inhibit tumorigeneicity of A549 non-small cell lung cancer tumor model in nude mice. Here we show that AG-1031, a small molecule identified by high throughput screening, can inhibit the double-stranded DNA binding activity of PC4, more effectively than its single-stranded DNA binding activity. AG-1031 also specifically inhibited PC4-dependent transcriptional activation in vitro using purified transcription factors. AG-1031 inhibited proliferation of several cultured cell lines derived from non-small cell lung cancers (NSCLC) and growth of tumors that formed from A549 cell xenografts in immuno-compromised mice. Moreover, pre-injection of AG-1031 in these mice not only reduced tumor size, but also prevented tumor formation in 20% of the animals. AG-1031 treated A549 cells and tumors from AG-1031 treated animals showed a significant decrease in the levels of both PC4 and VEGFC, a key mediator of angiogenesis in cancer. On the other hand, all tested mice remained constant weight during animal trials. These results demonstrated that AG-1031 could be a potential therapy for PC4-positive NSCLC.
Competing Interests: The authors YZ, AP, HC, NK, ZL and HG are affiliated to AscentGene, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare no conflicts of interest.
Databáze: MEDLINE
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