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Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress.

ABSTRACT: Sorafenib is the standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), but its use is hampered by the development of drug resistance. The activation of Akt by sorafenib is thought to be responsible for this resistance. Bufalin is the major active ingredient of the traditional Chinese medicine Chan su, which inhibits Akt activation; therefore, Chan su is currently used in the clinic to treat cancer. The present study aimed to investigate the ability of bufalin to reverse both inherent and acquired resistance to sorafenib. Bufalin synergized with sorafenib to inhibit tumor cell proliferation and induce apoptosis. This effect was at least partially due to the ability of bufalin to inhibit Akt activation by sorafenib. Moreover, the ability of bufalin to inactivate Akt depended on endoplasmic reticulum (ER) stress mediated by inositol-requiring enzyme 1 (IRE1). Silencing IRE1 with siRNA blocked the bufalin-induced Akt inactivation, but silencing eukaryotic initiation factor 2 (eIF2) or C/EBP-homologous protein (CHOP) did not have the same effect. Additionally, silencing Akt did not influence IRE1, CHOP or phosphorylated eIF2? expression. Two sorafenib-resistant HCC cell lines, which were established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition but were sensitive to bufalin. Thus, Bufalin reversed acquired resistance to sorafenib by downregulating phosphorylated Akt in an ER-stress-dependent manner via the IRE1 pathway. These findings warrant further studies to examine the utility of bufalin alone or in combination with sorafenib as a first- or second-line treatment after sorafenib failure for advanced HCC.

SUBMITTER: Zhai B

PROVIDER: S-EPMC4575108 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress.

Zhai Bo B Hu Fengli F Yan Haijiang H Zhao Dali D Jin Xin X Fang Taishi T Pan Shangha S Sun Xueying X Xu Lishan L

PloS one 20150918 9

Sorafenib is the standard first-line therapeutic treatment for patients with advanced hepatocellular carcinoma (HCC), but its use is hampered by the development of drug resistance. The activation of Akt by sorafenib is thought to be responsible for this resistance. Bufalin is the major active ingredient of the traditional Chinese medicine Chan su, which inhibits Akt activation; therefore, Chan su is currently used in the clinic to treat cancer. The present study aimed to investigate the ability ...[more]

PMID: 26381511

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Project description:BackgroundXanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known.MethodsThe effects of XAG on HCC cell proliferation and apoptosis were respectively examined by CCK-8 assay and Annexin V-FITC/PI apoptosis kit. Western blotting was conducted to detect the expression of proteins. The effect of XAG on the development of acidic vesicle organelles was assessed using acridine orange staining. mRFP-GFP-LC3 adenovirus was used to transfect HCC cells and the formation of autolysosome was detected using a confocal microscope.ResultsMechanistically, XAG promotes HCC cell death through triggering intrinsic apoptosis pathway, not extrinsic apoptotic pathway. Furthermore, XAG treatment induced autophagy in Bel 7402 and SMMC 7721 cells, as evidenced by an increase in autophagy-associated proteins, including LC3B-II, Beclin-1, and Atg5. Interestingly, inhibition of autophagy with 3-MA, Bafilomycin A1 (Baf A1), or siRNA targeting Atg5 effectively enhanced the apoptotic cell ratio in XAG-treated cells, indicating that protective effect of autophagy induced by XAG in HCC. Moreover, autophagy induced by XAG was mediated by activating endoplasmic reticulum stress (ERS), along with administration of XAG, the expression levels of ERS-associated proteins, including CHOP, GRP78, ATF6, p-eIF2α, IRE1α, and cleaved caspase-12 were significantly increased in HCC cells. Meanwhile, suppressing ERS with chemical chaperones (TUDCA) or CHOP shRNA could effectively abrogate the autophagy-inducing effect of XAG, and increase the apoptotic cell death. Further mechanistic studies showed that ERS-induced autophagy in XAG-treated cells was mediated by activation of JNK/c-jun pathway. XAG treatment resulted in the increase of p-JNK and p-c-jun, while suppressing ERS with TUDCA or CHOP shRNA could effectively reverse it. Meanwhile, SP600125, a JNK inhibitor, effectively reversed XAG-induced protective autophagy and enhanced cell apoptosis in XAG-treated HCC cells. In vivo results demonstrated that XAG exerts potent antitumor properties with low toxicity.ConclusionsCollectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC.

Dataset Information

Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress.

Publications

Bufalin Reverses Resistance to Sorafenib by Inhibiting Akt Activation in Hepatocellular Carcinoma: The Role of Endoplasmic Reticulum Stress.

Similar Datasets

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