Abstract
Reduced therapeutic efficacy of sorafenib, a first-generation multikinase inhibitor, is often observed during the treatment of advanced hepatocellular carcinoma (HCC). Emodin is an active component of Chinese herbs, and is effective against leukemia, lung cancer, colon cancer, pancreatic cancer, and HCC; however, the sensitizing effect of emodin on sorafenib-based HCC therapy has not been evaluated. Here, we demonstrate that emodin significantly improved the anti-cancer effect of sorafenib in HCC cells, such as HepG2, Hep3B, Huh7, SK-HEP-1, and PLC/PRF5. Mechanistically, emodin inhibits sterol regulatory element-binding protein-2 (SREBP-2) transcriptional activity, which suppresses cholesterol biosynthesis and oncogenic protein kinase B (AKT) signaling. Additionally, attenuated cholesterol synthesis and oncogenic AKT signaling inactivated signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. Furthermore, emodin synergistically increased cell cycle arrest in the G1 phase and apoptotic cells in the presence of sorafenib. Animal models xenografted with HepG2 or SK-HEP-1 cells also showed that the combination of emodin and sorafenib was sufficient to inhibit tumor growth. Overall, these results suggested that the combination of emodin and sorafenib may offer a potential therapy for patients with advanced HCC.
Highlights
Hepatocellular carcinoma (HCC), which is closely associated with chronic liver diseases, viral hepatitis and metabolic steatohepatitis, is the third most common cause of cancer-related deaths worldwide [1,2]
We have shown that the combination of emodin and sorafenib functioned synergistically to increase cell cycle arrest and the proportion of apoptotic cells, which was consistent with the observed decrease in cell viability, through the suppression of oncogenic AKT signaling and activation of signal transducer and activator of transcription 3 (STAT3) in HCC cells
We have proposed that the critical mechanism through which emodin sensitizes HCC cells to the anti-cancer effects of sorafenib is the suppression of AKT and STAT3 oncogenic growth signaling caused by decreases in intracellular cholesterol
Summary
Hepatocellular carcinoma (HCC), which is closely associated with chronic liver diseases, viral hepatitis and metabolic steatohepatitis, is the third most common cause of cancer-related deaths worldwide [1,2]. We found that the cholesterol-lowering effect of emodin, mediated through the suppression of SREBP-2 transcriptional activity and its target gene expression, was involved in the combined anti-cancer efficacy with sorafenib. We have proposed that the critical mechanism through which emodin sensitizes HCC cells to the anti-cancer effects of sorafenib is the suppression of AKT and STAT3 oncogenic growth signaling caused by decreases in intracellular cholesterol. Our in vitro and in vivo experimental findings indicated that the anti-cancer effect of emodin was mediated through the suppression of intracellular cholesterol levels, and subsequently caused the attenuation of oncogenic AKT and STAT3 pathways; in addition, we confirmed that this would provide a promising therapeutic strategy for improvement of the anti-cancer efficacy of sorafenib in patients with advanced HCC
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