Ivermectin suppresses tumour growth and metastasis through degradation of PAK1 in oesophageal squamous cell carcinoma

J Cell Mol Med. 2020 May;24(9):5387-5401. doi: 10.1111/jcmm.15195. Epub 2020 Mar 31.

Abstract

Oesophageal squamous cell carcinoma (ESCC), the most common form of oesophageal malignancies in the Asia-Pacific region, remains a major clinical challenge. In this study, we found that ivermectin, an effective antiparasitic drug that has been approved for patients to orally treat onchocerciasis for over 30 years, displayed potent antitumour activity against ESCC cells in vitro and in nude mice. We demonstrated that ivermectin significantly inhibited cell viability and colony formation, and induced apoptosis through a mitochondrial-dependent manner in ESCC cells. Ivermectin also abrogated ESCC cell migration, invasion, as well as the protein levels of MMP-2 and MMP-9. Mechanistically, ivermectin strongly inhibited the expression of PAK1; by further gain- and loss-of-function experiments, we confirmed that PAK1 played a crucial role in ivermectin-mediated inhibitory effects on ESCC cells. In addition, the data indicated that ivermectin promoted PAK1 degradation through the proteasome-dependent pathway. Additionally, ivermectin synergized with chemotherapeutic drugs including cisplatin and 5-fluorouracil to induce apoptosis of ESCC cells. Interestingly, the in vivo experiments also confirmed that ivermectin effectively suppressed tumour growth and lung metastasis of ESCC. Collectively, these results indicate that ivermectin exerts a potent antitumour activity against ESCC and is a promising therapeutic candidate drug for ESCC patients, even those carrying metastasis.

Keywords: PAK1; ivermectin; metastasis; oesophageal squamous cell carcinoma; tumour growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Esophageal Neoplasms / drug therapy*
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / pathology*
  • Esophageal Squamous Cell Carcinoma / drug therapy*
  • Esophageal Squamous Cell Carcinoma / genetics
  • Esophageal Squamous Cell Carcinoma / pathology*
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Ivermectin / pharmacology
  • Ivermectin / therapeutic use*
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Proteolysis* / drug effects
  • Signal Transduction / drug effects
  • Ubiquitin / metabolism
  • p21-Activated Kinases / metabolism*

Substances

  • Ubiquitin
  • Ivermectin
  • PAK1 protein, human
  • p21-Activated Kinases
  • Cisplatin
  • Fluorouracil