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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p53-induced gene 3 mediates cell death induced by glutathione peroxidase 3
Hui Wang1, Katherine Luo, Lang-Zhu Tan
1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Abstract:
Expression of glutathione peroxidase 3 (GPx3) is down-regulated in a variety of human malignancies. Both methylation and deletion of GPx3 gene underlie the alterations of GPx3 expression in prostate cancer. A strong correlation between the down-regulation of GPx3 expression and progression of prostate cancer and the suppression of prostate cancer xenografts in SCID mice by forced expression of GPx3 suggests a tumor suppression role of GPx3 in prostate cancer. However, the mechanism of GPx3-mediated tumor suppression remains unclear. In this report, GPx3 was found to interact directly with p53-induced gene 3 (PIG3). Forced overexpression of GPx3 in prostate cancer cell lines DU145 and PC3 as well as immortalized prostate epithelial cells RWPE-1 increased apoptotic cell death. Expression of GPx3(x73c), a peroxidase-negative OPAL codon mutant, in DU145 and PC3 cells also increased cell death. The induced expression of GPx3 in DU145 and PC3 cells resulted in an increase in reactive oxygen species and caspase-3 activity. These activities were abrogated by either knocking down PIG3 or mutating the PIG3 binding motif in GPx3 or binding interference from a peptide corresponding to PIG3 binding motif in GPx3. In addition, UV-treated RWPE-1 cells underwent apoptotic death, which was partially prevented by knocking down GPx3 or PIG3, suggesting that GPx3-PIG3 signaling is critical for UV-induced apoptosis. Taken together, these results reveal a novel signaling pathway of GPx3-PIG3 in the regulation of cell death in prostate cancer.
Insights
Glutathione peroxidase 3 (GPx3) interacts with PIG3 to promote cell death in prostate cancer. This GPx3-PIG3 signaling pathway is crucial for apoptosis, offering new therapeutic targets for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Signaling
Background:
- Glutathione peroxidase 3 (GPx3) expression is reduced in many cancers, including prostate cancer, suggesting a tumor suppressor role.
- The precise molecular mechanisms underlying GPx3's tumor suppressive functions, particularly in prostate cancer, are not fully understood.
Purpose of the Study:
- To elucidate the mechanism of GPx3-mediated tumor suppression in prostate cancer.
- To investigate the interaction between GPx3 and p53-induced gene 3 (PIG3) in regulating cell death.
Main Methods:
- Overexpression of GPx3 in prostate cancer cell lines (DU145, PC3) and immortalized prostate epithelial cells (RWPE-1).
- Utilizing a peroxidase-negative GPx3 mutant (GPx3(x73c)) and PIG3 knockdown.
- Assessing reactive oxygen species (ROS) levels, caspase-3 activity, and apoptotic cell death.
- Investigating UV-induced apoptosis in RWPE-1 cells with manipulated GPx3 and PIG3 levels.
Main Results:
- Forced GPx3 expression, including a mutant form, increased apoptosis in prostate cancer cells.
- GPx3 overexpression led to increased reactive oxygen species and caspase-3 activity, which were dependent on PIG3.
- GPx3 and PIG3 signaling was found to be critical for UV-induced apoptosis.
Conclusions:
- GPx3 directly interacts with PIG3, forming a novel signaling pathway that regulates cell death in prostate cancer.
- This GPx3-PIG3 pathway plays a significant role in apoptosis, potentially offering new therapeutic strategies for prostate cancer.
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