Abstract
Despite significant progress, advanced hepatocellular carcinoma (HCC) remains an incurable disease, and the overall efficacy of targeted therapy by Sorafenib remains moderate. We hypothesized that DCP (des-gamma-carboxy prothrombin), a prothrombin precursor produced in HCC, might be one of the reasons linked to the low efficacy of Sorafenib. We evaluated the efficacy of Sorafenib in HLE and SK-Hep cells, both of which are known DCP-negative HCC cell lines. In the absence of DCP, Sorafenib effectively inhibited the growth of HCC and induced cancer cell apoptosis. In the presence of DCP, HCC was resistant to Sorafenib-induced inhibition and apoptosis, as determined by in vitro assays and in mice xenografted with HLE cells. Molecular analysis of HLE xenografted-nude mice showed that DCP activates the transduction of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR cascades. DCP might stimulate the formation of compensatory feedback loops in the intricately connected signaling pathways when kinases are targeted by Sorafenib. Our results indicate that DCP antagonizes the inhibitory effects of Sorafenib on HCC through activation of the Ras/Raf/MEK/ERK and Ras/PI3K/Akt/mTOR signaling pathways. Taken together, our findings define a DCP-mediated mechanism of inhibition of Sorafenib in HCC, which is critical for targeting therapy in advanced HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide [1, 2]
We hypothesized that des-γ-carboxyl prothrombin (DCP), a prothrombin precursor produced in hepatocellular carcinoma (HCC), might be one of the reasons linked to the low efficacy of Sorafenib
Our results indicate that DCP antagonizes the inhibitory effects of Sorafenib on HCC through activation of the Ras/ Raf/MEK/ERK and Ras/PI3K/Akt/mTOR signaling pathways
Summary
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide [1, 2]. Several treatment modalities are available; only surgical resection and liver transplantation are considered curative, if diagnosed at an early stage. Since a majority of patients are diagnosed at an advanced stage, only 15% of patients are eligible for curative treatments, and they generally have a poor prognosis with median survival times of less than 1 year [1]. Among patients whose tumor characteristics are not appropriate for surgical therapy, systemic chemotherapy is still considered as an important strategy for improving survival. Chemotherapeutic agents include a variety of cytotoxic drugs and targeted therapeutic agents. Cytotoxic drugs have provided limited benefit for most HCC patients [2]. Targeted chemotherapy (ligands, membrane receptors and receptorassociated kinases) represents a promising strategy for the treatment of HCC. In 2007, the tyrosine kinase inhibitor (TKI) Sorafenib was approved by the Food and Drug Administration (FDA) for use in advanced HCC [3]
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