Drug resistance to
chemotherapy agents presents a major obstacle to the effective treatment of
hepatocellular carcinoma (HCC), a common type of
liver cancer. Increasing evidence indicates a link between drug resistance and the recurrence of HCC.
Polyphyllin I (PPI), a promising pharmaceutical candidate, has shown potential therapeutic advantages in the treatment of
sorafenib-resistant
hepatocellular carcinoma (SR-HCC cells). In this study, we sought to investigate the mechanism underlying the inhibitory effect of PPI on the invasion and
metastasis of SR-HCC cells. Our in vitro studies included scratch wound-healing migration assays and transwell assays to examine PPI's effect on HCC cell migration and invasion. Flow cytometry was employed to analyze the accumulation or efflux of
chemotherapy drugs. The results of these experiments demonstrated that PPI increased the susceptibility of HCC to
sorafenib while inhibiting SR-HCC cell growth, migration, and invasion. Molecular docking analysis revealed that PPI exhibited a higher binding affinity with
GRP78. Western blot analysis and immunofluorescence experiments showed that PPI reduced the expression of
GRP78,
E-cadherin,
N-cadherin,
Vimentin, and ABCG2 in SR-HCC cells. Interference with and overproduction of
GRP78 in vitro impacted the proliferation, migration, invasion, and
metastasis of HCC cells. Further examination revealed that PPI hindered the expression of
GRP78 protein, resulting in a suppressive effect on SR-HCC cell migration and invasion. Histological examination of
tumor tissue substantiated that administering PPI via gavage to HepG2/S xenograft nude mice inhibited
tumor growth and significantly reduced
tumor size, as evidenced by xenograft experiments involving nude mice.
Hematoxylin and
eosin (HE) staining of
tumor tissue specimens, along with immunohistochemistry (IHC), were conducted to evaluate the expression levels of Ki67,
GRP78,
N-cadherin,
Vimentin, and ABCG2. The results indicated that PPI administration decreased the levels of
proteins associated with
metastasis and markers of drug resistance in
tumor tissues, impeding
tumor growth and spread. Overall, our findings demonstrated that PPI effectively suppressed the viability, proliferation, invasion, and
metastasis of SR-HCC cells both in vitro and in vivo by modulating
GRP78 activity. These findings provide new insights into the mechanism of PPI inhibition of SR-HCC cell invasion and
metastasis, highlighting PPI as a potential treatment option for
sorafenib-resistant HCC.