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Sensitization of mesothelioma cells to platinum-based chemotherapy by GSTπ knockdown
Jianli Chen1, Charalambos Solomides2, Henry Simpkins1
1The Feinstein Institute for Medical Research, NS-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA; Department of Pathology and Laboratory Medicine at Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA.
Abstract:
It is predicted that the incidence of mesothelioma will increase and thus it is important to find new ways to treat this chemoresistant tumor. Glutathione-S-Transferase π (GSTπ) is found at significant levels in mesotheliomas and thus attenuating its intracellular levels may provide a means of sensitizing mesothelioma cells to chemotherapy. GSTπ knockdowns were therefore prepared with shRNA (less off-target effects) employing two cell lines (211H, H2452) that were typed by immunohistochemistry to be of mesothelial origin. The knockdowns exhibited a decrease in both total GST enzyme activity and GSTπ protein levels as well as an increase in both glutathione levels and sensitivity to cis and oxaliplatin. Cisplatin treatment of the knockdowns increased ROS levels significantly (as compared to the parental cells) and produced activation of the JNK/p38 pathways and activating transcription factor (ATF2). The degree of activation and increase in ROS appeared to correlate with the cell line's sensitivity to cisplatin. Treatment with N-Acetyl Cysteine decreased ROS production and JNK/p38 phosphorylation but had minimal affect on ATF2 suggesting a direct interaction of GTPπ with this transcription factor. Oxaliplatin treatment produced only minimal changes in ROS levels and activation of the JNK/p38 pathway. Recently, new methods of siRNA delivery (nanoparticles) have been shown to be effective in decreasing the levels of target proteins in humans including candidate genes involved in drug resistance - thus this approach may have promise in sensitizing cisplatin-resistant tumors to chemotherapy.
Insights
Targeting Glutathione-S-Transferase π (GSTπ) in mesothelioma may sensitize chemoresistant tumors. Reducing GSTπ levels increased sensitivity to cisplatin and oxaliplatin, offering new therapeutic strategies for mesothelioma.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Mesothelioma incidence is rising, necessitating novel treatments for this chemoresistant cancer.
- Glutathione-S-Transferase π (GSTπ) is upregulated in mesotheliomas, presenting a potential therapeutic target.
- Attenuating GSTπ may enhance mesothelioma cell sensitivity to chemotherapy.
Purpose of the Study:
- To investigate the role of GSTπ in mesothelioma chemoresistance.
- To determine if reducing GSTπ levels sensitizes mesothelioma cells to cisplatin and oxaliplatin.
- To explore the molecular mechanisms underlying GSTπ inhibition-induced chemosensitization.
Main Methods:
- Used shRNA to create GSTπ knockdowns in two mesothelial cell lines (211H, H2452).
- Assessed total GST activity, GSTπ protein levels, and glutathione levels.
- Evaluated cell sensitivity to cisplatin and oxaliplatin.
- Measured reactive oxygen species (ROS) levels and JNK/p38/ATF2 pathway activation.
Main Results:
- GSTπ knockdowns showed decreased GST activity and protein, with increased glutathione.
- Knockdowns exhibited enhanced sensitivity to cisplatin and oxaliplatin.
- Cisplatin treatment in knockdowns significantly increased ROS and activated JNK/p38/ATF2 pathways, correlating with sensitivity.
- N-Acetyl Cysteine reduced ROS and JNK/p38 phosphorylation, suggesting direct GSTπ-ATF2 interaction.
Conclusions:
- Reducing GSTπ levels can sensitize mesothelioma cells to platinum-based chemotherapy.
- GSTπ inhibition impacts ROS production and specific signaling pathways, potentially overcoming chemoresistance.
- Nanoparticle-mediated siRNA delivery offers a promising approach for targeting drug-resistant tumors like mesothelioma.
