Activation of the unfolded protein response contributed to the selective cytotoxicity of oroxylin A in human hepatocellular carcinoma HepG2 cells

Xu, Min; Lu, Na; Sun, Zhong-ying; Zhang, Haiwei; Dai, Qinsheng; Wei, Libin; Li, Zhiyu; You, Qidong; Guo, Qinglong

doi:10.1016/j.toxlet.2012.05.008

Cited by 29 publications

(35 citation statements)

References 59 publications

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“…Instead, many reports suggested the low toxicity and selectivity of OA. 35, 36 Our study proposed an underlying metabolism-modulating mechanism that implicated the antitumor effect of OA and recommended OA as a prospect for improving the current chemotherapeutic strategy for the therapeutic as well as preventative treatment of colon cancer.…”

Section: Discussionmentioning

confidence: 91%

Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism

Dai

et al. 2017

Cell Death Dis

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The occurrence and progress of colon cancer are closely associated with obesity. Therefore, the lipid metabolism, especially fatty acid metabolism, is a significant section of energy homeostasis in colon cancer cells, and it affects many important cellular processes. Oroxylin A is one of the main bioactive flavonoids of Scutellariae radix, which has a strong anticancer effect but low toxicity to normal tissue. In previous studies, we have proved that oroxylin A reprogrammes metabolism of cancer cells by inhibiting glycolysis. Here, we further investigated the metabolism-modulating effects of oroxylin A on the fatty acid metabolism in colon cancer cells under hypoxia. We found that HIF1α upregulated adipophilin, fatty acid synthase and sterol regulatory element-binding protein 1, and downregulated carnitine palmitoyltransferase 1 (CPT1), resulting in the promoted lipid uptake and transport, increased de novo fatty acid synthesis and suppressed fatty acid oxidation. Oroxylin A inactivated HIF1α and reprogrammed fatty acid metabolism of HCT116 cells, decreasing intracellular fatty acid level and enhancing fatty acid oxidation. Furthermore, the rapid decrease of fatty acid level caused by oroxylin A inhibited the nuclear translocation of β-cantenin and inactivated the Wnt pathway, arousing cell cycle arrest in G2/M phase. In vivo studies demonstrated that high-fat diet increased the incidence of colon cancer and accelerated tumor development. Importantly, besides the growth inhibitory effects on colon cancer xenograft, oroxylin A prevented carcinogenesis and delayed progress of primary colon cancer as well. Our studies enriched the metabolic regulatory mechanism of oroxylin A, and suggested that oroxylin A was a potent candidate for the treatment and prevention of colorectal cancer.

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Section: Discussionmentioning

confidence: 91%

Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism

Dai

et al. 2017

Cell Death Dis

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“…Hepatic cell line L0254, hepatocellular carcinoma (HCC) cell lines Huh7 and HepG255, hepatic cell line QGY-7703 and HCC cell line QSG-7701 which were isolated from the same hepatocellular carcinoma patient56, were purchased from the Type Culture Collection of the Chinese Academy of Sciences, Shanghai, China. All cells were cultured in Dulbecco’s Modified Eagle Medium (Gibco) containing 10% fetal bovine serum (Gibco), 100 μg/mL streptomycin sodium and 100 U/mL penicillin G sodium (MP Biomedicals) at 37 °C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

Huang

Zhou

et al. 2016

Sci Rep

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Due to the lack of effective treatment, hepatocellular carcinoma (HCC) is one of the malignancies with low survival rates worldwide. Combination of hyperthermia and chemotherapy has shown promising results in several abdominal tumours, but high expression of HSP90 in tumours attenuated the efficacy of hyperthermia. Thus a combination of hyperthermia and inhibition of HSP90 might be a feasible therapeutic strategy for HCC. One hepatic cell line (L02) and two HCC cell lines (Huh7 and HepG2) were heated at 42 °C for 0, 0.5 or 4 h with or without 100 nM 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). HCC cells of the combination group exhibited more G2/M arrest and higher apoptotic rates which might result from suffering from more reactive oxygen species and serious DNA damage. Heat shock/17-DMAG co-treatment of HCC cells also destabilized CDK1, Cyclin B1 and CDC25C with a concomitant decreased proportion of cells in the M phase. Furthermore, co-treatment impaired the interaction of HSP90α with CDC37 and with CDK1, accompanied with decreased soluble CDK1. Combination of 17-DMAG with a 1.5-h whole body hyperthermia treatment attenuated tumour growth in xenograft mice models. These results suggest hyperthermia sensitize HCC to 17-DMAG, and combination of hyperthermia with 17-DMAG might be a potential therapeutic strategy for HCC.

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“…The shRNA interference for stable knockdown of the CHOP gene in wt‐HepG2 and wt‐SMMC cells was performed as described previously . The GADD153 shRNA plasmid was used to knockdown the CHOP gene, whereas the Control shRNA plasmid‐A encoded with a scrambled sequence was used as the negative control.…”

Section: Methodsmentioning

confidence: 99%

“…Flow cytometry (FCM) assays for cell death types (apoptosis and necrosis) were performed as described previously . After double‐staining with fluorescent dyes annexin V‐fluorescein isothiocyanate (FITC) and propidium iodide, the cell death types were identified by the FACSCalibur (BD Biosciences, San Jose, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT

Zhang

et al. 2013

Hepatology Research

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Activation of the unfolded protein response contributed to the selective cytotoxicity of oroxylin A in human hepatocellular carcinoma HepG2 cells

Cited by 29 publications

References 59 publications

Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism

Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism

Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition

Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT

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