Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptormediated induction of connexin 43

J. L. Munoz, V. Rodriguez-Cruz, S. J. Greco, S. H. Ramkissoon, K. L. Ligon, P. Rameshwar

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM.

Original languageEnglish (US)
Article numbere1145
JournalCell Death and Disease
Volume5
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

Keywords

  • Connexin 43
  • Glioblastoma
  • Immune therapy
  • Resistance
  • Stem cell
  • Temozolomide EGF receptor

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptormediated induction of connexin 43'. Together they form a unique fingerprint.

Cite this