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Article | Open Access

Apatinib modulates sorafenib-resistant hepatocellular carcinoma through inhibiting the EGFR/JNK/ERK signaling pathway

DEXUE FAN#,1, WEI SU#,2, ZHAOWEN BI3, XINXING WANG1, XIANWEN XU1, MINGZE MA4, LICHAO ZHU5, ZHENHAI ZHANG1,3( ), JUNLIN GAO2( )
Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
Liver Gall Bladder and Pancreatic Surgery Ward, Qinghai Red Cross Hospital, Xining, 810001, China
Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China
Departments of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
Department of Pediatric Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China

#These two authors contributed equally to this work

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Abstract

Objectives

Apatinib has been reported to be a promising treatment for sorafenib-resistant hepatocellular carcinoma (HCC) patients. However, the underlying mechanism remains ambiguous. The study aimed to explore the efficacy of apatinib in sorafenib-resistant HCC and the underlying mechanism both in vitro and in vivo.

Methods

After observing epithelial-mesenchymal transformation (EMT) changes in HepG2 and HepG2/Sorafenib cells, we treated them with varying concentrations of apatinib to assess its impact on sorafenib-resistant HCC. Subsequently, specific inhibitors of c-Jun N-terminal kinase (JNK, SP600125) and extracellular signal-regulated kinase (ERK, PD98059) were introduced to investigate whether apatinib influenced sorafenib-resistant HCC via modulation of the epidermal growth factor receptor (EGFR)/JNK/ERK signaling pathway in vitro and in vivo. Biological behavior changes were assessed through cell counting kit-8 (CCK-8), colony formation, transwell, and immunofluorescence tests. Simultaneously, Western blot analysis was conducted to elucidate the expression of proteins associated with EMT and the EGFR/JNK/ERK signaling pathway.

Results

The HepG2/Sorafenib cells exhibited greater resistance to sorafenib compared to HepG2 cells, and sorafenib-resistant HCC was characterized by EMT changes. Apatinib demonstrated concentration-dependent inhibition of biological behaviors in HepG2/Sorafenib cells, with minimal impact on HepG2 cells. Additionally, apatinib had a pronounced effect on the expression of EMT-related proteins in sorafenib-resistant cells similar to that in sorafenib-sensitive cells. Furthermore, there was a dose-dependent reduction in the expression of proteins associated with the EGFR/JNK/ERK pathway in apatinib-treated groups. Notably, SP600125 and PD98059 contributed to the inhibition of EMT and EGFR/JNK/ERK pathway-related proteins by apatinib in sorafenib-resistant HCC.

Conclusion

Apatinib potentially hindered the progression of sorafenib-resistant HCC by suppressing both EMT and the EGFR/JNK/ERK pathway.

Keywords

ApatinibSorafenib resistanceEGFR/JNK/ERKEpithelial mesenchymal transformationHepatocellular carcinoma (HCC)

References

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Oncology Research
Volume 33 Issue 6,
May 2025
Pages 1459-1472
DOI: 10.32604/or.2025.060407

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Cite this article:
FAN D, SU W, BI Z, et al. Apatinib modulates sorafenib-resistant hepatocellular carcinoma through inhibiting the EGFR/JNK/ERK signaling pathway. Oncology Research, 2025, 33(6): 1459-1472. https://doi.org/10.32604/or.2025.060407

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Received: 31 October 2024
Accepted: 03 January 2025
Published: 29 May 2025
© The Author 2024.

This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.