Ascochlorin Suppresses MMP-2-Mediated Migration and Invasion by Targeting FAK and JAK-STAT Signaling Cascades

J Cell Biochem. 2018 Jan;119(1):300-313. doi: 10.1002/jcb.26179. Epub 2017 Jul 4.

Abstract

Human glioblastomas express higher levels of matrix metalloprotease-2 (MMP-2) than low-grade brain tumors and normal brain tissues. Ascochlorin (ASC) has anti-metastatic, anti-angiogenic, and synergistic effect in various types of cancer cells. However, it remains unknown whether ASC can affect cell migration and invasion in malignant human glioma cells. In this study, we found that ASC indeed inhibits cell migration and invasion in U373MG and A172. ASC significantly suppresses the MMP-2 gelatinolytic activity and expression in U373MG and A172. To determine the molecular mechanism by which ASC suppressed cell migration and invasion, we investigated whether ASC could modulate metastasis via focal adhesion kinase (FAK) and janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, a potential drug target. ASC strongly inhibits the phosphorylation of FAK, and treatment with a FAK inhibitor significantly suppresses cancer cell migration in the presence of ASC. In addition, ASC significantly decreased phosphorylation of JAK2/STAT3, cancer cell migration and nuclear translocation of STAT3. Taken together, these results suggest that ASC inhibits cell migration and invasion by blocking FAK and JAK/STAT signaling, resulting in reduced MMP-2 activity. J. Cell. Biochem. 119: 300-313, 2018. © 2017 Wiley Periodicals, Inc.

Keywords: ASCOCHLORIN; BRAIN CANCER; INVASION; MIGRATION; MMP-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / pharmacology*
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Focal Adhesion Kinase 1 / metabolism*
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology
  • Glioblastoma / pathology
  • Humans
  • Janus Kinase 2 / metabolism*
  • Matrix Metalloproteinase 2 / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Proteins / metabolism*
  • Phenols / pharmacology*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*

Substances

  • Alkenes
  • Neoplasm Proteins
  • Phenols
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Focal Adhesion Kinase 1
  • JAK2 protein, human
  • Janus Kinase 2
  • PTK2 protein, human
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • ascochlorin