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• W4312013670 abstract "Abstract Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) are deadly malignancy with poor prognosis and limited treatment options. Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis and development of malignant solid tumors which is associated with chemotherapeutic drug resistance. The therapeutic potential of targeting ER stress signaling in cancer via surface BiP/GRP78 (78-kDa glucose-regulated protein), a major role in ER stress sensing, is now under clinical trials. YUM70 is a novel inducer of ER stress that induces apoptosis in cancer by directly bound BiP and inactivated its function. In this study, we investigated the possible role of epidermal growth factor receptor (EGFR) pathway and cell death mechanisms in YUM70 induced CCA or HCC cells cytotoxicity. Although both YUM70 and HA15 as BiP inhibitors exerted the mono-therapeutic anti-proliferation effect and induced autophagy and apoptosis, YUM70 exhibited more potent anti-tumor potential by suppressing the EGFR downstream signaling: ERK1/2 and mTOR/p70(S6K) pathways at the concentration of 100 µM more effectively. At the same tested concentration, HA15 could not inhibit the phosphorylation of ERK1/2 or p70(S6K). Moreover, we discovered that YUM70 induced GSDME dependent pyroptosis by activating NF-κB pathway and inhibited EMT via inactivation of β-catenin pathway. Additionally, pharmacologic targeting of ERK signaling is usually limited by adaptive resistance, frequently mediated by feedback activation of receptor tyrosine kinases (RTKs) signaling. We observed that treatment of HuCCT1 or Huh7 cells with YUM70 resulted in increased EGFR phosphorylation. Inhibiting EGFR activation with Gefitinib or Osimertinib synergistically increased the anti-tumor activity of BiP inhibitors. Our results demonstrated novel strategy that BiP inhibitors, in combination with Gefitinib or Osimertinib, should be tested in CCA or HCC patients." @default.
• W4312013670 created "2023-01-03" @default.
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• W4312013670 date "2022-12-09" @default.
• W4312013670 modified "2023-10-03" @default.
• W4312013670 title "One Novel BiP/GRP78 Inhibitor YUM70 Induces GSDME Dependent Pyroptosis and Enhances Sensitivity To EGFR Inhibitors in cholangiocarcinoma and hepatocellular carcinoma" @default.
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• W4312013670 doi "https://doi.org/10.21203/rs.3.rs-2349164/v1" @default.
• W4312013670 hasPublicationYear "2022" @default.
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