Abstract
Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance-associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. Mol Cancer Ther; 16(12); 2711-23. ©2017 AACR.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common aggressive types of tumor worldwide
We have demonstrated that lycorine represses Akt/ mTOR signaling via decreasing the levels of tongue cancer resistance–associated protein 1 (TCRP1) protein, which results in activating apoptotic and autophagic processes and leading to suppressing the growth of HCC in vitro and in vivo
We have found that lycorine initiates apoptotic cell death in HCC cells, which is supported by the results of DAPI staining and V-FITC/PI double staining
Summary
Hepatocellular carcinoma (HCC) is one of the most common aggressive types of tumor worldwide. HCC is a highly mortal tumor and its median survival rate remains under 1 year after diagnosis [1, 2]. HCC is a heterogeneous disease originated from chronic liver diseases, such as chronic inflammation and cirrhosis. The therapeutic strategy against HCC is mainly composed of resection, transplantation, local ablation, and chemotherapy [3, 4]. Because early symptoms of HCC are not obvious, most patients with HCC are diagnosed at advanced stages and are unsuitable for potentially curative therapies such as resection, transplantation, and local ablation [5,6,7]. Sorafenib, a small-molecule multikinase inhibitor, Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)
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