Recombinant VP1, an Akt inhibitor, suppresses progression of hepatocellular carcinoma by inducing apoptosis and modulation of CCL2 production

• Published in: PloS one 2011-08, Vol.6 (8), p.e23317-e23317
• Main Authors: Chen, Tai-An, Wang, Jui-Ling, Hung, Shao-Wen, Chu, Chiao-Li, Cheng, Yung-Chih, Liang, Shu-Mei
• Format: Article
• Language: English
• Subjects: Activation; Agricultural biotechnology; AKT protein; Analysis; Animal models; Animals; Anticancer properties; Antitumor activity; Apoptosis; Apoptosis - drug effects; BAX protein; Biology; Biotechnology; Blotting, Western; Breast cancer; Cancer; Cancer metastasis; Cancer therapies; Capsid protein; Capsid Proteins - pharmacology; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell migration; Cell proliferation; Chemical compounds; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - metabolism; Chemokines; Chemotherapy; Colorectal cancer; Cytokines; Data processing; Deactivation; Development and progression; Dissociation; Flow Cytometry; Foot & mouth disease; Foot and mouth disease; Gene therapy; Growth factors; Health aspects; Hepatocellular carcinoma; Hepatocytes; Immunohistochemistry; Immunoprecipitation; Inhibition; Intravenous administration; Kinases; Ligands; Liver cancer; Liver Neoplasms - metabolism; Medical prognosis; Medical research; Medicine; Metastases; Metastasis; Mice; Mitochondria; Monocyte chemoattractant protein 1; NF-κB protein; Pharmacology; Phosphorylation; Prostate cancer; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Recombinant proteins; Recombinant Proteins - pharmacology; Rodents; Transcription factors; Translocation; Tumor cell lines; Tumor necrosis factor-TNF; Tumorigenesis; Viability; Viral proteins; Viruses; VP1 protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023317

The 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. Treatment 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. The 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.