The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma. Academic Article uri icon

Overview

abstract

  • Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, studied the role of the Par3 protein (encoded by PARD3) in GBM. GBM patient transcriptomic data and patient-derived culture analysis indicated diverse levels of expression of PARD3 across and independent from subtypes. Multiplex immunolocalization in GBM tumors identified Par3 protein enrichment in SOX2-, CD133-, and NESTIN-positive (stem-like) cells. Analysis of GBM cultures of the three subtypes (proneural, classical, mesenchymal), revealed decreased gliomasphere forming capacity and enhanced invasiveness upon silencing Par3. GBM cultures with suppressed Par3 showed low expression of stemness (SOX2 and NESTIN) but higher expression of differentiation (GFAP) genes. Moreover, Par3 silencing reduced the expression of a set of genes encoding mitochondrial enzymes that generate ATP. Accordingly, silencing Par3 reduced ATP production and concomitantly increased reactive oxygen species. The latter was required for the enhanced migration observed upon silencing of Par3 as anti-oxidants blocked the enhanced migration. These findings support the notion that Par3 exerts homeostatic redox control, which could limit the tumor cell-derived pool of oxygen radicals, and thereby the tumorigenicity of GBM.

authors

  • Shahidi Dadras, Mahsa
  • Caja, Laia
  • Mezheyeuski, Artur
  • Liu, Sijia
  • Gélabert, Caroline
  • Gomez-Puerto, Maria Catalina
  • Gallini, Radiosa
  • Rubin, Carl-Johan
  • Ten Dijke, Peter
  • Heldin, Carl-Henrik
  • Moustakas, Aristidis

publication date

  • October 12, 2021

Research

keywords

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cell Polarity
  • Cell Self Renewal
  • Glioblastoma

Identity

PubMed Central ID

  • PMC8511086

Scopus Document Identifier

  • 85117405321

Digital Object Identifier (DOI)

  • 10.1002/path.5026

PubMed ID

  • 34642295

Additional Document Info

volume

  • 12

issue

  • 10