Curcumin derivative WZ35 inhibits tumor cell growth via ROS-YAP-JNK signaling pathway in breast cancer

J Exp Clin Cancer Res. 2019 Nov 8;38(1):460. doi: 10.1186/s13046-019-1424-4.

Abstract

Background: Breast cancer is the most prevalent cancer among women worldwide. WZ35, an analog of curcumin, has been demonstrated to remarkably improve the pharmacokinetic profiles in vivo compared with curcumin. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. However, antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear.

Methods: CCK8, Flow cytometry and transwell assays were used to measure cell proliferation, cell cycle arrest, apoptosis, cell migration and invasion. We constructed xenograft mouse model and lung metastasis model to assess the antitumor activities of WZ35 in vivo. To explore the underlying molecular mechanisms of WZ35, we performed a series of overexpression and knockdown experiments. The cellular oxygen consumption rates (OCRs) was measured to assess mitochondrial dysfunction.

Results: We found that treatment of breast cancer cells with WZ35 exerts stronger anti-tumor activities than curcumin both in vitro and in vivo. Mechanistically, our research showed that WZ35 induced reactive oxygen species (ROS) generation and subsequent YAP mediated JNK activation in breast cancer cells. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP and JNK activation. In addition, ROS mediated YAP and JNK activation induced mitochondrial dysfunction in breast cancer cells.

Conclusion: Our study showed that novel anti-cancer mechanisms of WZ35 in breast cancer cells and ROS-YAP-JNK pathway might be a potential therapeutic target for the treatment of breast cancer patients.

Keywords: Breast Cancer; JNK; Mitochondrial dysfunction; ROS; WZ35; YAP.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Curcumin / analogs & derivatives*
  • Curcumin / pharmacology
  • Disease Models, Animal
  • Female
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • Oxidative Phosphorylation / drug effects
  • Prognosis
  • Reactive Oxygen Species / metabolism*
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • Reactive Oxygen Species
  • Transcription Factors
  • WZ35 compound
  • YAP1 (Yes-associated) protein, human
  • JNK Mitogen-Activated Protein Kinases
  • Curcumin