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 language | English (US) |
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Pages (from-to) | 733-751 |
Number of pages | 19 |
Journal | Anti-cancer drugs |
Volume | 17 |
Issue number | 7 |
DOIs | |
State | Published - Aug 2006 |
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