Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum

Yongxian Ma, Ren Qi Yuan, Saijun Fan, Changyan Hu, Itzhak D. Goldberg, John J. Laterra, Eliot M. Rosen

Research output: Contribution to journalArticle

Abstract

Scatter factor (hepatocyte growth factor) and its receptor c-Met are increasingly expressed during progression from low-grade to high-grade gliomas. Scatter factor/c-Met signaling induces glioma cell motility, invasion, angiogenesis and resistance to DNA-damaging agents. The latter is relevant to the understanding of the resistance of human gliomas to chemotherapy and radiotherapy. The goal of this study was to identify a set of genes that may contribute to scatter factor-mediated protection of U373MG cells against cis-platinum, a DNA cross-linking agent. We used DNA microarray assays, confirmatory semiquantitative reverse transcription-polymerase chain reaction analysis and functional assays to identify genes involved in the scatter factor-induced resistance of U373MG to cis-platinum. We identified a group of genes that are overexpressed in cells treated with scatter factor plus cis-platinum relative to cells treated with cis-platinum alone and confirmed some of these gene expression alterations by reverse transcription-polymerase chain reaction. Inhibiting the expression of three of these genes - polycystic kidney disease 1, amplified in breast cancer 1 and DEAD/H box helicase 21 - using small interfering RNAs reduced survival of cis-platinum-treated cells and partially reversed the scatter factor protection against cis-platinum. Dominant-negative Akt and IκB super-repressor expression vectors inhibited the scatter factor protection, and abrogated the ability of scatter factor to alter the expression of DEAD/H box helicase 21 and polycystin (PKD1) within the context of cis-platinum exposure. The Akt and nuclear factor-κB inhibitors had no effect on amplified in breast cancer 1 expression. These studies implicate DEAD/H box helicase 21, polycystin (PKD1) and amplified in breast cancer 1 as novel transcription-dependent regulators of scatter factor-mediated glioma cell protection against cytotoxic death, and identify other potential regulators for future study.

Original languageEnglish (US)
Pages (from-to)733-751
Number of pages19
JournalAnti-cancer drugs
Volume17
Issue number7
DOIs
StatePublished - Aug 1 2006

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Keywords

  • Akt
  • Amplified in breast cancer 1
  • DEAD/H box helicase 21
  • Glioma
  • Hepatocyte growth factor
  • Nuclear factor-κB
  • Polycystic kidney disease 1
  • Scatter factor
  • U373MG
  • cis-platinum

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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