Related Experiment Video
Updated: Jul 30, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib
Qiu-Chen Bi1, Zhi-Qiang Deng2, Yang-Feng Lv1
1Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China; Institute for Advanced Study, Nanchang University, Nanchang, China.
Abstract:
Sorafenib is a tyrosine kinase inhibitor for the treatment of advanced-stage HCC; however, clinical trials of sorafenib failed to demonstrate long-term survival benefits due to drug resistance. Low Pi stress has been shown to inhibit tumor growth and the expression of multidrug resistance-associated proteins. In this study, we investigated the sensitivity of HCC to sorafenib under conditions of low Pi stress. As a result, we found that low Pi stress facilitated sorafenib-mediated suppression of migration and invasion of HepG-2 and Hepa1-6 cells by decreasing the phosphorylation or expression of AKT, Erk and MMP-9. Angiogenesis was inhibited due to decreased expression of PDGFR under low Pi stress. Low Pi stress also decreased the viability of sorafenib-resistant cells by directly regulating the expression of AKT, HIF-1a and P62. In vivo drug sensitivity analysis in the four animal models showed a similar tendency that low Pi stress enhances sorafenib sensitivity in both the normal and drug-resistant models. Altogether, low Pi stress enhances the sensitivity of hepatocellular carcinoma to sorafenib and expands the indications for sevelamer.
Insights
Low phosphate (Pi) stress enhances hepatocellular carcinoma (HCC) sensitivity to sorafenib, a tyrosine kinase inhibitor. This approach improves treatment efficacy in both normal and drug-resistant HCC models.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer death.
- Sorafenib, a tyrosine kinase inhibitor, is a standard treatment for advanced HCC but faces challenges with drug resistance and limited long-term survival benefits.
- Low phosphate (Pi) stress has demonstrated potential in inhibiting tumor growth and multidrug resistance-associated proteins.
Purpose of the Study:
- To investigate the impact of low Pi stress on the sensitivity of HCC cells and models to sorafenib.
- To elucidate the molecular mechanisms underlying the enhanced sorafenib efficacy under low Pi conditions.
Main Methods:
- Utilized HepG-2 and Hepa1-6 cell lines to assess sorafenib sensitivity under low Pi stress.
- Analyzed the expression and phosphorylation of key signaling molecules including AKT, Erk, MMP-9, PDGFR, HIF-1a, and P62.
- Conducted in vivo studies using four animal models to evaluate drug sensitivity.
Main Results:
- Low Pi stress significantly enhanced sorafenib's ability to suppress migration and invasion in HCC cells by downregulating AKT, Erk, and MMP-9.
- Angiogenesis was inhibited under low Pi stress due to reduced PDGFR expression.
- Low Pi stress decreased the viability of sorafenib-resistant HCC cells by modulating AKT, HIF-1a, and P62.
- In vivo experiments confirmed that low Pi stress improves sorafenib sensitivity in both normal and drug-resistant HCC animal models.
Conclusions:
- Low phosphate stress is a promising strategy to enhance the therapeutic efficacy of sorafenib in hepatocellular carcinoma.
- This approach may overcome sorafenib resistance and improve treatment outcomes for HCC patients.
- The findings suggest potential expanded indications for sevelamer, a phosphate binder, in conjunction with sorafenib therapy.
