Piperlongumine inhibits hepatocellular carcinoma growth by modulating GSTP1 and restraining the STAT3 signaling pathway

Abstract

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, underscoring the need for effective treatments. Purpose: This study aimed to investigate the growth-inhibitory effects of piperlongumine (PIP) on HCC and identify the key gene responsible for its action. Study Design: This study explored the molecular mechanisms underlying PIP’s suppression of HCC. Methods: To evaluate the inhibitory effect of PIP, HCC cell lines and nude mice models with human HCC xenografts were employed. Western blot analysis was used to determine the protein levels of glutathione-S-transferase P1 (GSTP1) and signal transducer and activator of transcription 3 (STAT3) following PIP intervention. Cell function analysis was conducted by manipulating the GSTP1 gene through overexpression or knockout. Additionally, immunoprecipitation was utilized to probe the ability of STAT3 to bind to GSTP1. Results: Exposure to PIP led to an increased dissociation of GSTP1 dimers and a reduction in p-STAT3 levels in HCC cells. Knockout of GSTP1 attenuated the inhibitory effect of PIP on HCC growth, while overexpression of GSTP1 heightened the sensitivity of HCC cells to PIP. Moreover, PIP enhanced the interaction between GSTP1 and STAT3. This study provides insights into PIP’s role in inhibiting HCC growth. It effectively modulates structural changes in the GSTP1 protein, resulting in an enhanced ability of STAT3 to bind to GSTP1 and the suppression of the STAT3 signaling pathway. Conclusion: These findings suggest that GSTP1 may serve as a pivotal gene in PIP-based HCC treatment. The novel insights gained from this research pave the way for the exploration of effective therapeutic strategies.

Keywords

• Piperlongumine
• GSTP1
• STAT3
• Hepatocellular carcinoma
• Tumor growth