Targeting suppression of AKT activation boosts chemosensitivity of hepatocarcinoma cells via regulation of inflammation and metastasis: Functional protection of Rehmapicroside

• TRIM21 restrains migration, invasion and inflammation of HCC cells through blocking AKT signaling. • Rehmapicroside reduces proliferation and induces G2/M phase in HCC cells. • Rehmapicroside induces apoptosis and suppresses tumor growth. • Rehmapicroside inhibits EMT in HCC cells. Hepatocellular carcinoma (HCC) is the most common malignant tumors with poor prognosis and few effective therapeutic strategies. Although cisplatin (cDDP) is the first-line chemotherapy for HCC, its application has been limited due to drug resistance and side effects. Rehmapicroside (Reh) is a major active principle of the root of Radix Rehmanniae that has anti-tumor effects. In the present study, we uncovered the role of Reh in modulating chemosensitivity of cDDP in HCC. We found that combinational treatments of Reh and cDDP significantly reduced the cell proliferation of HCC cells at relatively lower concentrations for each drug. Cell cycle arrest in G2/M phase was markedly induced in HCC cells co-treated with Reh and cDDP compared with cDDP alone group. In addition, Reh dramatically enhanced the capacity of cDDP to induce apoptosis in HCC cells through increasing Caspase-3 cleavage. Co-treatment with Reh and cDDP effectively suppressed tumor growth in xenograft mouse models of HCC without adverse effects. Moreover, migration and invasion of HCC cells were significantly restrained by combinational treatments of Reh and cDDP. Mechanistically, tripartite motif protein 21-phosphatidylinositol 3-kinase/protein kinase B (TRIM21-PI3K/AKT) signaling pathway was considerably impeded in HCC cells and tumor tissues by Reh and cDDPco-treatment. Notably, we found that constitutive activation of AKT almost completely abrogated the capacity of Reh plus cDDP to inhibit cell proliferation, migration, and invasion. Collectively, our results demonstrated that combinational therapy of Reh and cDDP may be a novel and effective therapeutic strategy for HCC treatment.