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Polyphyllin I exerts anti-hepatocellular carcinoma activity by targeting ZBTB16 to activate the PPARγ/RXRα signaling
Lu Shan1,2, Yijun Chen3, Guo An4
1Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
Background:
Studies have reported that polyphyllin I (PPI) had effective anti-tumor activity against hepatocellular carcinoma (HCC). However, the precise molecular mechanism of this action and the direct target remain unclear. The aim of this study was to discover the molecular targets and the exact mechanism of PPI in the treatment of HCC.
Methods:
Various HCC cells and Zebrafish xenotransplantation models were used to examine the efficacy of PPI against HCC. A proteome microarray, surface plasmon resonance (SPR) analysis, small molecule transfection, and molecular docking were conducted to confirm the direct binding targets of PPI. Transcriptome and Western blotting were then used to determine the exact responding mechanism. Finally, the anticancer effect and its precise mechanism, as well as the safety of PPI, were verified using a mouse tumor xenograft study.
Results:
The results demonstrated that PPI had significant anticancer activity against HCC in both in vitro studies of two cells and the zebrafish model. Notably, PPI selectively enhanced the action of the Zinc finger and BTB domain-containing 16 (ZBTB16) protein by directly binding to it. Furthermore, specific knockdown of ZBTB16 markedly attenuated PPI-dependent inhibition of HCC cell proliferation and migration caused by overexpression of the gene. The transcriptome and Western blotting also confirmed that the interaction between ZBTB16 and PPI also activated the PPARγ/RXRα pathway. Finally, the mouse experiments confirmed the efficacy and safety of PPI to treat HCC.
Conclusions:
Our results indicate that ZBTB16 is a promising drug target for HCC and that PPI as a potent ZBTB16 agonist has potential as a therapeutic agent against HCC by regulating the ZBTB16/PPARγ/RXRα signaling axis.
Insights
Polyphyllin I (PPI) effectively targets hepatocellular carcinoma (HCC) by binding to Zinc finger and BTB domain-containing 16 (ZBTB16). This interaction activates the ZBTB16/PPARγ/RXRα pathway, offering a potential new therapy for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) remains a significant health concern.
- Polyphyllin I (PPI) has shown anti-tumor activity against HCC, but its mechanism is unclear.
- Identifying PPI's molecular targets is crucial for developing effective HCC therapies.
Purpose of the Study:
- To elucidate the molecular targets and mechanism of action of Polyphyllin I (PPI) in hepatocellular carcinoma (HCC).
- To investigate the potential of PPI as a therapeutic agent for HCC.
Main Methods:
- In vitro and in vivo HCC models (cell lines, zebrafish, mouse xenografts) were used.
- Proteome microarray, SPR, and molecular docking identified PPI's direct binding targets.
- Transcriptome and Western blotting analyzed the molecular mechanism.
- Zebrafish and mouse models assessed efficacy and safety.
Main Results:
- PPI demonstrated significant anticancer activity against HCC in vitro and in vivo.
- PPI directly binds to and enhances the activity of Zinc finger and BTB domain-containing 16 (ZBTB16).
- PPI-induced inhibition of HCC was dependent on ZBTB16 and activated the PPARγ/RXRα pathway.
Conclusions:
- ZBTB16 is a promising drug target for HCC treatment.
- PPI acts as a potent ZBTB16 agonist, offering therapeutic potential for HCC.
- The ZBTB16/PPARγ/RXRα signaling axis is a key pathway targeted by PPI in HCC.
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