4.8 Article

G-quadruplex inducer/stabilizer pyridostatin targets SUB1 to promote cytotoxicity of a transplatinum complex

Journal

NUCLEIC ACIDS RESEARCH
Volume 50, Issue 6, Pages 3070-3082

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkac151

Keywords

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Funding

  1. National Natural Science Foundation of China [21927804, 21635008, 21790390, 21790392, 21127901, 22004121]
  2. National Key Research and Development Program of China [2018YFA0800903]
  3. China Postdoctoral Science Foundation [2020M680675]
  4. Youth Innovation Promotion Association of Chinese Academy of Sciences [2017051]
  5. BMS [2019BMS20012]

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Using MS proteomics strategy, this study uncovered the complex regulation of gene expression by PDS in HeLa cancer cells, and also revealed the impact of PDS on cell cycle regulation. Furthermore, the downregulation of PC4 was found to enhance the cytotoxicity of a platinum anticancer drug towards HeLa cells.
Pyridostatin (PDS) is a well-known G-quadruplex (G4) inducer and stabilizer, yet its target genes have remained unclear. Herein, applying MS proteomics strategy, we revealed PDS significantly downregulated 22 proteins but upregulated 16 proteins in HeLa cancer cells, of which the genes both contain a number of G4 potential sequences, implying that PDS regulation on gene expression is far more complicated than inducing/stabilizing G4 structures. The PDS-downregulated proteins consequently upregulated 6 proteins to activate cyclin and cell cycle regulation, suggesting that PDS itself is not a potential anticancer agent, at least toward HeLa cancer cells. Importantly, SUB1, which encodes human positive cofactor and DNA lesion sensor PC4, was downregulated by 4.76-fold. Further studies demonstrated that the downregulation of PC4 dramatically promoted the cytotoxicity of trans-[PtCl2(NH3)(thiazole)] (trans-PtTz) toward HeLa cells to a similar level of cisplatin, contributable to retarding the repair of 1,3-trans-PtTz crosslinked DNA lesion mediated by PC4. These findings not only provide new insights into better understanding on the biological functions of PDS but also implicate a strategy for the rational design of novel multi-targeting platinum anticancer drugs via conjugation of PDS as a ligand to the coordination scaffold of transplatin for battling drug resistance to cisplatin.

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