w09, a novel autophagy enhancer, induces autophagy-dependent cell apoptosis via activation of the EGFR-mediated RAS-RAF1-MAP2K-MAPK1/3 pathway

Autophagy
Pinghu ZhangHongqi Liu

Abstract

The EGFR (epidermal growth factor receptor) signaling pathway is frequently deregulated in many malignancies. Therefore, targeting the EGFR pathway is regarded as a promising strategy for anticancer drug discovery. Herein, we identified a 2-amino-nicotinonitrile compound (w09) as a novel autophagy enhancer, which potently induced macroautophagy/autophagy and consequent apoptosis in gastric cancer cells. Mechanistic studies revealed that EGFR-mediated activation of the RAS-RAF1-MAP2K-MAPK1/3 signaling pathway played a critical role in w09-induced autophagy and apoptosis of gastric cancer cells. Inhibition of the MAPK1/3 pathway with U0126 or blockade of autophagy by specific chemical inhibitors markedly attenuated the effect of w09-mediated growth inhibition and caspase-dependent apoptosis. Furthermore, these conclusions were supported by knockdown of ATG5 or knockout of ATG5 and/or ATG7. Notably, w09 increased the expression of SQSTM1 by transcription, and knockout of SQSTM1 or deleting the LC3-interaction region domain of SQSTM1, significantly inhibited w09-induced PARP1 cleavage, suggesting the central role played by SQSTM1 in w09-induced apoptosis. In addition, in vivo administration of w09 effectively inhibited tumor growth...Continue Reading

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Citations

May 9, 2018·International Journal of Molecular Sciences·Md Ariful IslamPinghu Zhang
Sep 5, 2018·Liver International : Official Journal of the International Association for the Study of the Liver·Wen-Yuan LiHui Guo
Mar 27, 2018·International Journal of Cancer. Journal International Du Cancer·Mopa Alina SooroPinghu Zhang
Sep 19, 2019·Cancers·Yoojung KwonDooil Jeoung
May 8, 2020·International Journal of Molecular Sciences·Karel Vališ, Petr Novák
Jul 25, 2020·Future Medicinal Chemistry·Pinghu ZhangDongping Wei
Dec 5, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Pinghu ZhangXiaohui Yang
Sep 16, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Du FengDu Zhen-Xian
May 2, 2021·Journal of Experimental & Clinical Cancer Research : CR·Li LiTingxiu Xiang

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Methods Mentioned

BETA
surgical resection
xenografts
fluorescence
confocal microscopy
transmission electron microscopy
phase contrast microscopy
FACS
flow cytometry
PCR
transfection

Software Mentioned

GraphPad
ImageJ
Quality One

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