Abstract
Hepatocellular carcinoma (HCC) is one of the most serious and deadly diseases worldwide with limited options for effective treatment. Biomarker-based active compound targeting therapy may shed some light on novel drugs for HCC. The endoplasmic reticulum (ER) stress and unfolded protein response (UPR) play important roles in the regulation of cell fate and have become novel signaling targets for the development of anticancer drugs. Celastrol, a triterpene from traditional Chinese medicine, has been reported to possess anti-tumor effects on various cancers. We, along with several other research groups, have recently reported that UPR was induced by celastrol in several different cancers, including hepatocellular carcinoma. However, UPR status in HCC still remains unclear. The role of ER stress and autophagy in response to celastrol also has yet to be elucidated. Our results demonstrated that celastrol could cause G2/M phase rest and inhibit proliferation in HepG2 and Bel7402. Exposure to celastrol resulted in the activation of the intrinsic apoptotic pathway, via ER stress and the UPR. In murine syngeneic model studies celastrol inhibited H22 tumor growth via the induction of ER stress and apoptosis. Our study suggests that celastrol is a potential drug for HCC therapy via targeting ER-stress/UPR.
Highlights
Hepatocellular carcinoma (HCC) is a very common form of cancer and is associated with an extremely poor prognosis; HCC is the third most common cause of cancerrelated deaths worldwide [1, 2]
Our findings demonstrate that celastrol induced apoptotic endoplasmic reticulum (ER) stress signaling and autophagy and suppressed HCC cell proliferation
Colony-forming assays were performed to test the effect of celastrol on growth kinetics; HepG2 and Bel7402 cells were seeded at a low density and treated with increasing concentrations of celastrol
Summary
Hepatocellular carcinoma (HCC) is a very common form of cancer and is associated with an extremely poor prognosis; HCC is the third most common cause of cancerrelated deaths worldwide [1, 2]. HCC is prevalent in Asia and sub-Saharan Africa where 80% of worldwide cases occur [2, 3]. More than 80% of HCC patients present with advanced disease, and the treatment options available to these patients are very limited and the prognosis is dire [5]. There are a variety of drugs (e.g., sorafenib) used in the treatment of the disease, many of them are quickly rendered ineffective due to resistance [6].
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