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

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Elsevier Science
      Original Publication: Oxford, New York [etc.] Paragamon Press.
    • Subject Terms:
      DNA-Binding Proteins/*metabolism ; Everolimus/*pharmacology ; Lung Neoplasms/*metabolism ; Receptor, Notch3/*metabolism ; TOR Serine-Threonine Kinases/*metabolism ; Transcription Factor CHOP/*metabolism ; Transcription Factors/*metabolism; A549 Cells ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Apoptosis/physiology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/physiology ; Everolimus/therapeutic use ; HEK293 Cells ; Humans ; Lung Neoplasms/drug therapy ; TOR Serine-Threonine Kinases/antagonists & inhibitors
    • Abstract:
      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.
      Competing Interests: 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.
      (Copyright © 2020 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Apoptosis; CHOP; Lung cancer; Notch 3; c-MYC
    • Accession Number:
      0 (Antineoplastic Agents)
      0 (DDIT3 protein, human)
      0 (DNA-Binding Proteins)
      0 (MYCBP protein, human)
      0 (NOTCH3 protein, human)
      0 (Receptor, Notch3)
      0 (Transcription Factors)
      147336-12-7 (Transcription Factor CHOP)
      9HW64Q8G6G (Everolimus)
      EC 2.7.1.1 (MTOR protein, human)
      EC 2.7.11.1 (TOR Serine-Threonine Kinases)
    • Publication Date:
      Date Created: 20200324 Date Completed: 20201022 Latest Revision: 20211204
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/j.bcp.2020.113921
    • Accession Number:
      32201213