RETRACTED ARTICLE: Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1012-z) contains supplementary material, which is available to authorized users.

RETRACTED: Soyasapogenol B Attenuates Laryngeal Carcinoma Progression through Inducing Apoptotic and Autophagic Cell Death

“…For example, autophagy induced by hispidulin has been found to alleviate sevoflurane‐induced neuronal apoptosis (Huang et al, ). A recent study also reported that autophagy‐mediated by ER stress abrogated the proapoptotic effect of Xanthoangelol in hepatocellular carcinoma (Li et al, ). Autophagy can not only block the induction of apoptosis by inhibiting the activation of apoptosis‐associated caspase but can also help to induce apoptosis.…”

“…Natural compounds and their derivatives have been shown to play an irreplaceable role in the discovery of new drugs with high‐efficiency and low‐toxicity (Ahmed and Ishibashi, ; Li et al, ). Several classes of compounds such as saponins, flavonoids, alkaloids, and polyphenols from natural products have been investigated for their anticancer activities (Han et al, ).…”

RETRACTED:Alpinumisoflavone suppresses human Glioblastoma cell growth and induces cell cycle arrest through activating peroxisome proliferator‐activated receptor‐γ

“…The human GBM cell lines U373 and T98G were obtained from the Centre for Cell Resources of Shanghai Institutes for Life Sciences, Chinese Academy of Sciences (Shanghai, China). The cells were cultured and maintained in RPMI‐1640 medium with specific conditions, incubated in a humidified incubator at 37°C, 5% CO 2 (Li et al, ), and regularly operated by an inverted microscope. AIF (C20H16O5, purity: >99%) was obtained from Nu‐chek Prep (Elysian, MN).…”

RETRACTED ARTICLE: Physcion 8-O-β-glucopyranoside mediates the NLRP3-associated pyroptosis and cell metastasis in the human osteosarcoma cells via ER stress activation

“…The Editor in Chief retracted this article (1) because of significant concerns regarding a number of images presented in Figure 6c, which question the integrity of the data. It appears a number of the histopathology images have been published previously in unrelated articles (2,3,4). In additional, it appears that an image used in Figure 1c (SAOS-2 at 0uM) has also appeared in unrelated articles with different labels (5,6).…”