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0404 inhibits hepatocellular carcinoma through a p53/miR-34a/SIRT1 positive feedback loop

Caixia Xia1,2, Liyan Shui1, Guohua Lou1

  • 1The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.

Scientific Reports
|July 2, 2017
PubMed

Insights

A new DNA-damaging compound, 0404, shows promise for treating hepatocellular carcinoma (HCC). It activates the p53/miR-34a/SIRT1 pathway, promoting cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Hepatocellular carcinoma (HCC) remains a significant challenge with limited effective chemotherapeutic options.
  • DNA-damaging agents are a historical approach in cancer therapy, but their efficacy in HCC is suboptimal.

Purpose of the Study:

  • To screen and evaluate a novel DNA-damaging compound, 0404, for its anti-cancer effects against HCC.
  • To elucidate the molecular mechanisms underlying the anti-cancer activity of 0404 in HCC.

Main Methods:

  • Utilized time-dependent cellular response profiling (TCRP) to identify compound 0404.
  • Employed human HCC cell lines and a mouse xenograft model to assess anti-cancer efficacy.
  • Conducted transcriptome and miRNA array analyses to determine the mechanism of action.

Main Results:

  • Compound 0404 demonstrated anti-cancer effects in HCC cell lines and xenografts.
  • 0404 up-regulated miR-34a expression and p53 protein levels while decreasing SIRT1 levels in HepG2 cells.
  • The p53 signaling pathway, particularly miR-34a, was identified as crucial for 0404's activity.

Conclusions:

  • Compound 0404 represents a potential therapeutic agent for HCC, especially in tumors with wild-type p53.
  • The anti-cancer effects are mediated through a p53/miR-34a/SIRT1 feedback loop, inducing apoptosis.
  • Further investigation into 0404 could lead to novel HCC treatment strategies.

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