PMID- 32201213 OWN - NLM STAT- MEDLINE DCOM- 20201022 LR - 20211204 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 175 DP - 2020 May TI - Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus. PG - 113921 LID - S0006-2952(20)30149-0 [pii] LID - 10.1016/j.bcp.2020.113921 [doi] AB - The mammalian target of rapamycin (mTOR) pathway converges diverse environmental cues to support the lung cancer growth and survival. However, the mTOR-targeted mono-therapy does not achieve expected therapeutic effect. Here, we revealed that fangchinoline (FCL), an active alkaloid that purified from the traditional Chinese medicine Stephania tetrandra S. Moore, enhanced the anti-lung cancer effect of mTOR inhibitor everolimus (EVE). The combination of EVE and FCL was effective to activate Notch 3, and subsequently evoked its downstream target c-MYC. The blockage of Notch 3 signal by the molecular inhibitor of gamma-secretase or siRNA of Notch 3 reduced the c-MYC expression and attenuated the combinational efficacy of EVE and FCL on cell apoptosis and proliferation. Moreover, the c-MYC could bind to the C/EBP homologous protein (CHOP) promoter and facilitate CHOP transcription. The conditional genetic deletion of CHOP reduced the apoptosis on lung cancer cells to the same degree as blockage of Notch 3/c-MYC axis, providing further evidence for that the Notch 3/c-MYC axis regulates the transcription of CHOP and finally induces apoptosis upon co-treatment of FCL and EVE in lung cancer cells. Overall, our findings, to the best of our knowledge, firstly link CHOP to Notch 3/c-MYC axis-dependent apoptosis and provide the Notch 3/c-MYC/CHOP activation as a promising strategy for mTOR-targeted combination therapy in lung cancer treatment. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Li, Ting AU - Li T AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Xu, Xiao-Huang AU - Xu XH AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Guo, Xia AU - Guo X AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Yuan, Tao AU - Yuan T AD - Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. FAU - Tang, Zheng-Hai AU - Tang ZH AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Jiang, Xiao-Ming AU - Jiang XM AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Xu, Yu-Lian AU - Xu YL AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Zhang, Le-Le AU - Zhang LL AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Chen, Xiuping AU - Chen X AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Zhu, Hong AU - Zhu H AD - Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. FAU - Shi, Jia-Jie AU - Shi JJ AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. FAU - Lu, Jin-Jian AU - Lu JJ AD - State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address: jinjianlu@um.edu.mo. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200319 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Antineoplastic Agents) RN - 0 (DDIT3 protein, human) RN - 0 (DNA-Binding Proteins) RN - 0 (MYCBP protein, human) RN - 0 (NOTCH3 protein, human) RN - 0 (Receptor, Notch3) RN - 0 (Transcription Factors) RN - 147336-12-7 (Transcription Factor CHOP) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - A549 Cells MH - Antineoplastic Agents/pharmacology/therapeutic use MH - Apoptosis/drug effects/physiology MH - Cell Line, Tumor MH - DNA-Binding Proteins/*metabolism MH - Drug Resistance, Neoplasm/drug effects/physiology MH - Everolimus/*pharmacology/therapeutic use MH - HEK293 Cells MH - Humans MH - Lung Neoplasms/drug therapy/*metabolism MH - Receptor, Notch3/*metabolism MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Transcription Factor CHOP/*metabolism MH - Transcription Factors/*metabolism OTO - NOTNLM OT - Apoptosis OT - CHOP OT - Lung cancer OT - Notch 3 OT - c-MYC COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/03/24 06:00 MHDA- 2020/10/23 06:00 CRDT- 2020/03/24 06:00 PHST- 2019/12/31 00:00 [received] PHST- 2020/03/17 00:00 [accepted] PHST- 2020/03/24 06:00 [pubmed] PHST- 2020/10/23 06:00 [medline] PHST- 2020/03/24 06:00 [entrez] AID - S0006-2952(20)30149-0 [pii] AID - 10.1016/j.bcp.2020.113921 [doi] PST - ppublish SO - Biochem Pharmacol. 2020 May;175:113921. doi: 10.1016/j.bcp.2020.113921. Epub 2020 Mar 19.