Identification of Vaccinia-H1 Related Phosphatase as an Anticancer Target for 1,2,3,4,6-O-Pentagalloylglucose
Sun-Young Yoon1, Do-Hwi Kim1, Kyung Min Roh2
1School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
Abstract:
Protein tyrosine phosphatases are involved in diverse human diseases, including cancer, diabetes and inflammatory disorders. Loss of Vaccinia-H1 related phosphatase (VHR) has been shown to arrest at the G1-S and G2-M transitions of the cell cycle, and to increases cell death of prostate cancer cells through JNK activation, suggesting that VHR can be considered as an anticancer target. In this study, 658 natural products were screened through in vitro enzyme assay to identify VHR inhibitor. Among the VHR-inhibitory compounds, 1,2,3,4,6-O-pentagalloylglucose (PGG) was selected for further study as it has been reported to show antitumor effects against tumor model mice, but its direct target has not been identified. PGG inhibited the catalytic activity of VHR (Ki =53 nm) in vitro. Furthermore, the incubation of HeLa cervical cancer cells with PGG dramatically decreased cell viability and markedly increased the protein levels of the cleaved PARP, a hallmark of apoptosis. In addition, treatment of HeLa cells with PGG significantly reduced the protein levels of cyclin D1, Bcl-2 and STAT3 phosphorylation. Taken together, these results suggest that PGG could be a potential therapeutic candidate for the treatment of cervical cancer through VHR inhibition.
Insights
1,2,3,4,6-O-pentagalloylglucose (PGG) inhibits Vaccinia-H1 related phosphatase (VHR), a potential anticancer target. PGG shows promise as a therapeutic for cervical cancer by inducing apoptosis and reducing tumor cell viability.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein tyrosine phosphatases (PTPs) are implicated in various diseases, including cancer.
- Vaccinia-H1 related phosphatase (VHR) dysregulation is linked to cell cycle arrest and cancer cell death, identifying it as an anticancer target.
Purpose of the Study:
- To screen natural products for VHR inhibitors.
- To investigate the potential of 1,2,3,4,6-O-pentagalloylglucose (PGG) as a VHR-targeted therapeutic for cervical cancer.
Main Methods:
- In vitro enzyme assay screening of 658 natural products to identify VHR inhibitors.
- Biochemical characterization of PGG's inhibition of VHR catalytic activity.
- Assessment of PGG's effects on HeLa cervical cancer cell viability, apoptosis markers (cleaved PARP), and key protein levels (cyclin D1, Bcl-2, STAT3 phosphorylation).
Main Results:
- PGG was identified as a potent VHR inhibitor with a Ki of 53 nm.
- PGG significantly reduced HeLa cell viability and induced apoptosis, evidenced by increased cleaved PARP.
- PGG treatment decreased cyclin D1, Bcl-2, and STAT3 phosphorylation in HeLa cells.
Conclusions:
- PGG exhibits direct VHR inhibitory activity.
- PGG demonstrates potential as a therapeutic agent for cervical cancer by inducing apoptosis and inhibiting key cell survival pathways.
- VHR inhibition by PGG offers a novel therapeutic strategy for cervical cancer treatment.
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