Activation of notch 3/c-MYC/CHOP axis regulates apoptosis and promotes sensitivity of lung cancer cells to mTOR inhibitor everolimus

• Published in: Biochemical pharmacology 2020-05, Vol.175, p.113921-113921, Article 113921
• Main Authors: Li, Ting, Xu, Xiao-Huang, Guo, Xia, Yuan, Tao, Tang, Zheng-Hai, Jiang, Xiao-Ming, Xu, Yu-Lian, Zhang, Le-Le, Chen, Xiuping, Zhu, Hong, Shi, Jia-Jie, Lu, Jin-Jian
• Format: Article
• Language: English
• Subjects: Apoptosis; c-MYC; CHOP; Lung cancer; Notch 3
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2020.113921

[Display omitted] 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 γ-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.