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Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
Silencing of Glutathione S-Transferase Pi Inhibits Cancer Cell Growth via Oxidative Stress Induced by Mitochondria
Naoki Fujitani1, Akihiro Yoneda2, Motoko Takahashi1
1Department of Biochemistry, Sapporo Medical University School of Medicine, S1W17, Sapporo, 060-8556, Japan.
Abstract:
Antitumor drug development based on the concept of intervening in the antioxidant system of cancer cells has been gaining increased interest. In this study, we propose a promising strategy for cancer treatment using modulation of oxidative stress by suppression of glutathione S-transferases (GSTs), a typical antioxidant enzyme. siRNA which can be applied to the development of nucleic acid drugs, enabling them to eliminate unwanted side effects, increase specificity, and avoid the problem of drug resistance, was employed for GSTP-silencing at the transcriptional level. The silencing of the pi class of GST (GSTP) that displayed the most characteristic expression profile in 13 kinds of cancer cell lines has shown significant impairment in the growth of cancer cells due to oxidative stress caused by excess ROS accumulation. Comparative proteomics between normal cells and GSTP-silenced pancreatic cancer cell PANC-1 suggested that GSTP-silencing facilitated the mitochondrial dysfunction. These findings show promise for the development of strategies toward cancer therapy based on the mechanism that allows genetic silencing of GSTP to promote oxidative stress through mitochondria dysfunction.
Insights
Targeting antioxidant enzymes like glutathione S-transferases (GSTs) offers a novel cancer treatment. Suppressing GST P (GSTP) using siRNA induces oxidative stress and impairs cancer cell growth by affecting mitochondria.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Antitumor drug development increasingly focuses on modulating cancer cell antioxidant systems.
- Glutathione S-transferases (GSTs) are key antioxidant enzymes targeted for cancer therapy.
- Oxidative stress plays a critical role in cancer progression and treatment resistance.
Purpose of the Study:
- To investigate the potential of suppressing glutathione S-transferase P (GSTP) as a cancer treatment strategy.
- To evaluate the effects of GSTP silencing on cancer cell growth and oxidative stress.
- To explore the underlying mechanisms, including mitochondrial dysfunction, involved in GSTP-silenced cancer cells.
Main Methods:
- Utilized small interfering RNA (siRNA) for transcriptional silencing of GSTP.
- Examined the impact of GSTP silencing on cancer cell growth across 13 cancer cell lines.
- Performed comparative proteomics on normal cells versus GSTP-silenced pancreatic cancer cells (PANC-1).
Main Results:
- GSTP silencing significantly impaired the growth of various cancer cell lines.
- Suppression of GSTP led to increased reactive oxygen species (ROS) accumulation and oxidative stress.
- Comparative proteomics indicated that GSTP silencing induced mitochondrial dysfunction in pancreatic cancer cells.
Conclusions:
- Genetic silencing of GSTP is a promising strategy for cancer therapy.
- Modulating oxidative stress via GSTP suppression promotes cancer cell death.
- Mitochondrial dysfunction is a key mechanism through which GSTP silencing exerts its antitumor effects.
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