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 2006

Fingerprint

Hepatocyte Growth Factor
Glioblastoma
Cisplatin
Genes
Glioma
TRPP Cation Channels
Cytoprotection
Breast Neoplasms
Reverse Transcription
Proto-Oncogene Proteins c-met
Gene Expression
Polycystic Kidney Diseases
Polymerase Chain Reaction
DNA
Oligonucleotide Array Sequence Analysis
Small Interfering RNA
Cell Movement
Radiotherapy
Drug Therapy

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum. / Ma, Yongxian; Yuan, Ren Qi; Fan, Saijun; Hu, Changyan; Goldberg, Itzhak D.; Laterra, John J; Rosen, Eliot M.

In: Anti-Cancer Drugs, Vol. 17, No. 7, 08.2006, p. 733-751.

Research output: Contribution to journalArticle

Ma, Yongxian ; Yuan, Ren Qi ; Fan, Saijun ; Hu, Changyan ; Goldberg, Itzhak D. ; Laterra, John J ; Rosen, Eliot M. / Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum. In: Anti-Cancer Drugs. 2006 ; Vol. 17, No. 7. pp. 733-751.
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AB - 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.

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