Abstract

BackgroundThe application of viral elements in tumor therapy is one facet of cancer research. Recombinant capsid protein VP1 (rVP1) of foot-and-mouth disease virus has previously been demonstrated to induce apoptosis in cancer cell lines. Here, we aim to further investigate its apoptotic mechanism and possible anti-metastatic effect in murine models of hepatocellular carcinoma (HCC), one of the most common human cancers worldwide.Methodology/Principal FindingsTreatment with rVP1 inhibited cell proliferation in two murine HCC cell lines, BNL and Hepa1-6, with IC50 values in the range of 0.1–0.2 µM. rVP1 also induced apoptosis in these cells, which was mediated by Akt deactivation and dissociation of Ku70-Bax, and resulted in conformational changes and mitochondrial translocation of Bax, leading to the activation of caspases-9, -3 and -7. Treatment with 0.025 µM rVP1, which did not affect the viability of normal hepatocytes, suppressed cell migration and invasion via attenuating CCL2 production. The production of CCL2 was modulated by Akt-dependent NF-κB activation that was decreased after rVP1 treatment. The in vivo antitumor effects of rVP1 were assessed in both subcutaneous and orthotopic mouse models of HCC in immune-competent BALB/c mice. Intratumoral delivery of rVP1 inhibited subcutaneous tumor growth as a result of increased apoptosis. Intravenous administration of rVP1 in an orthotopic HCC model suppressed tumor growth, inhibited intra-hepatic metastasis, and prolonged survival. Furthermore, a decrease in the serum level of CCL2 was observed in rVP1-treated mice.Conclusions/SignificanceThe data presented herein suggest that, via inhibiting Akt phosphorylation, rVP1 suppresses the growth, migration, and invasion of murine HCC cells by inducing apoptosis and attenuating CCL2 production both in vitro and in vivo. Recombinant protein VP1 thus has the potential to be developed as a new therapeutic agent for HCC.

Highlights

  • Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [1]

  • We reported that Recombinant capsid protein VP1 (rVP1) induces apoptosis in breast and prostate cancer cell lines [13]

  • To investigate whether rVP1 holds any potential for treatment of hepatocellular carcinoma (HCC), we first examined its effect on cell growth and induction of apoptosis in HCC cells

Read more

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [1]. the etiology of HCC has been largely explained, HCC is still a focus of cancer research due to its poor prognosis and high rates of recurrence resulting from local invasion and intra-hepatic metastasis [2,3]. The Ras/Raf/Mek/Erk and PI3K/Akt/mTOR signaling pathways are important in hepatocarcinogenesis, and several inhibitors targeting those pathways are currently under clinical development [4,5,6,7]. Despite these advances, the continued investigation of new therapeutic modalities for HCC is warranted due to the shortage of effective systemic therapy for advanced cases and the highly unfavorable prognosis of the disease. We aim to further investigate its apoptotic mechanism and possible anti-metastatic effect in murine models of hepatocellular carcinoma (HCC), one of the most common human cancers worldwide

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call