Inorganic Chemistry

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

Authors

  • Yinzhu Hou Institute of Chemistry, the Chinese Academy of Sciences ,
  • Tieliang Gan Institute of Chemistry, the Chinese Academy of Sciences ,
  • Tiantian Fang Institute of Chemistry, the Chinese Academy of Sciences ,
  • Yao Zhao Institute of Chemistry, the Chinese Academy of Sciences ,
  • Qun Luo Institute of Chemistry, the Chinese Academy of Sciences ,
  • Xingkai Liu Institute of Chemistry, the Chinese Academy of Sciences ,
  • Luyu Qi Institute of Chemistry, the Chinese Academy of Sciences ,
  • Yanyan Zhang Institute of Chemistry, the Chinese Academy of Sciences ,
  • Feifei Jia Institute of Chemistry, the Chinese Academy of Sciences ,
  • Juanjuan Han Institute of Chemistry, the Chinese Academy of Sciences ,
  • Shumu Li Institute of Chemistry, the Chinese Academy of Sciences ,
  • Shijun Wang Shandong University of Traditional Chinese Medicine ,
  • Fuyi Wang Institute of Chemistry, the Chinese Academy of Sciences

Abstract

Pyridostatin (PDS) is a well-known G-quadruplex (G4) inducer and stabilizer, yet its target genes have remained unclear. Herein, combining mass spectrometry based proteomics strategy with bioinformatics analysis, we revealed that PDS significantly downregulated 22 proteins, of which the genes contain rich G4 potential sequences, in HeLa cancer cells, consequently upregulating 16 proteins remarkably. The PDS-regulated proteins appeared to work synergistically to activate cyclin and cell cycle regulation, and to restrain the inhibition of ARE-mediated mRNA decay pathway, suggesting that PDS itself is not a potential anticancer agent, at least towards HeLa cancer. Importantly, among the PDS targeted genes, SUB1, which expresses the human positive cofactor and DNA lesion sensor PC4, was down-regulated by 4.76-fold. Further studies demonstrated that the downregulation of PC4 dramatically promoted the cytotoxicity of trans-[PtCl2(NH3)(thiazole)] towards HeLa cells to a similar level to that of cisplatin, contributable to retarding the repair of 1,3-trans-platinated 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.

Content

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Supplementary material

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G-quadruplex inducer/stabilizer pyridostatin targets SUB1 to promote cytotoxicity of a transplatinum complex
Supplementary Figures S1 - S4 and Tables S1 - S4.