Phragmunis a suppresses glioblastoma through the regulation of MCL1-FBXW7 by blocking ELK1-SRF complex-dependent transcription

Neurochem Int. 2021 Jul:147:105051. doi: 10.1016/j.neuint.2021.105051. Epub 2021 May 9.

Abstract

Glioblastoma (GBM) is a highly aggressive brain tumor. During screening work, we found a new compound named phragmunis A (PGA), which is derived from the fruitbody of Trogia venenata, exhibits a potential cytotoxic effect on patient-derived recurrent GBM cells and temozolomide (TMZ)-resistant cell lines. The present study was designed to investigate the potential molecular mechanism of the anti-glioma effects of PGA in vitro and in vivo. Studies investigating the mechanism revealed that PGA diminished the binding efficiency of ETS family of transcription factor (ELK1) and Serum response factor (SRF), and suppressed ELK1-SRF complex-dependent transcription, which decreased the transcriptional levels of downstream genes Early growth response protein 1 (EGR1)-Polycomb ring finger (BMI1), thus inducing the imbalanced regulation between Myeloid cell leukaemia-1 (MCL1) and F-Box and WD repeat domain containing 7 (FBXW7). Finally, orthotopic xenograft models were established to confirm the anti-glioma effect of PGA on tumour growth. We showed, for the first time, that the cytotoxic effects of PGA occurred by inducing MCL1 inhibition and FBXW7 activation by blocking ELK1-SRF complex-dependent transcription. The blockage of ELK1-mediated transcription resulted in the suppression of EGR1-BMI1, which led to the upregulation of FBXW7 expression and downregulation of MCL1. These findings suggested that PGA could be a therapeutic drug candidate for the treatment of recurrent GBM by targeting the ELK1-SRF complex.

Keywords: ELK1; FBXW7; MCL1; Phragmunis A; SRF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • F-Box-WD Repeat-Containing Protein 7 / drug effects*
  • F-Box-WD Repeat-Containing Protein 7 / metabolism
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / physiology
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Myeloid Cell Leukemia Sequence 1 Protein / drug effects
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Plant Extracts / pharmacology*
  • Serum Response Factor / drug effects
  • Serum Response Factor / metabolism
  • ets-Domain Protein Elk-1 / drug effects
  • ets-Domain Protein Elk-1 / metabolism

Substances

  • ELK1 protein, human
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Plant Extracts
  • SRF protein, human
  • Serum Response Factor
  • ets-Domain Protein Elk-1