GHR knockdown enhances the sensitivity of HCC cells to sorafenib
Shuang Gao1, Qianwen Ni2, Xiuli Wu3
1Department of Gastroenterology, The Third Affiliated Hospital of Naval Military Medical University, Shanghai 201800, China.
Abstract:
Sorafenib is approved for treatment of advanced hepatocellular carcinoma (HCC) by the Drug Administration. However, the efficacy of sorafenib has become very limited because most tumors have developed resistance to this drug. In this study, we found that sorafenib stimulated GHR expression in HCC cell lines. Thus, GHR might be linked to sorafenib resistance. To verify this hypothesis, we researched the roles of GHR knockdown and sorafenib combination in cell viability, apoptosis, cycle, and migration. The results showed that GHR blockage enhanced sorafenib blocking of cell cycle progression, leading to inhibition of this drug on HCC cell viability, and the improved promoting ability of sorafenib on cell apoptosis. In addition, it was found that GHR knockdown enhanced sorafenib inhibition of cell migration. The synergistic antitumor effects of sorafenib and GHR knockdown combination may be attributed to inhibition of PI3K/AKT/ERK1/2 signaling pathway. In conclusion, the findings suggest that GHR knockdown enhances the sensitivity of HCC cells to sorafenib. and the inactivation of PI3K/AKT/ERK1/2 signaling pathway may be the underlying mechanisms. This highlights the absence of GHR as a promising way to enhance sorafenib efficacy in HCC.
Insights
Sorafenib resistance in hepatocellular carcinoma (HCC) may be overcome by targeting GHR expression. Blocking GHR enhances sorafenib
Area of Science:
- Oncology
- Molecular Biology
- Hepatology
Background:
- Sorafenib is a standard treatment for advanced hepatocellular carcinoma (HCC).
- Tumor resistance significantly limits sorafenib's long-term efficacy.
- Sorafenib treatment was observed to increase Growth Hormone Receptor (GHR) expression in HCC cells, suggesting a link to resistance.
Purpose of the Study:
- To investigate the role of GHR in sorafenib resistance in HCC.
- To evaluate the therapeutic potential of combining GHR knockdown with sorafenib treatment.
Main Methods:
- Utilized HCC cell lines to study the effects of GHR knockdown and sorafenib.
- Assessed impacts on cell viability, apoptosis, cell cycle progression, and migration.
- Analyzed the involvement of the PI3K/AKT/ERK1/2 signaling pathway.
Main Results:
- GHR knockdown potentiated sorafenib's ability to inhibit cell cycle progression and reduce HCC cell viability.
- Combined GHR blockage and sorafenib significantly enhanced cancer cell apoptosis.
- GHR knockdown augmented sorafenib's inhibitory effect on cancer cell migration.
- Synergistic antitumor effects were associated with the inhibition of the PI3K/AKT/ERK1/2 pathway.
Conclusions:
- GHR knockdown enhances HCC cell sensitivity to sorafenib.
- Inactivation of the PI3K/AKT/ERK1/2 signaling pathway is a key mechanism underlying this synergy.
- Targeting GHR represents a promising strategy to improve sorafenib efficacy in HCC treatment.
