12-Deoxyphorbol Esters Induce Growth Arrest and Apoptosis in Human Lung Cancer A549 Cells Via Activation of PKC-δ/PKD/ERK Signaling Pathway.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Apoptosis/*drug effects ; Carcinogens/*pharmacology ; Cell Proliferation/*drug effects ; Phorbol Esters/*pharmacology ; Signal Transduction/*drug effects; A549 Cells ; Carcinogens/chemistry ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Phorbol Esters/chemistry ; Protein Kinase C/metabolism ; Protein Kinase C-delta/metabolism
    • Abstract:
      Prostratin, a non-tumor promoting 12-deoxyphorbol ester, has been reported as a protein kinase C (PKC) activator and is shown to have anti-proliferative activity in certain cancer cell types. Here we show that GRC-2, a prostratin analogue isolated from Euphorbia grandicornis , is ten-fold more potent than prostratin for inhibiting the growth of human non-small cell lung cancer (NSCLC) A549 cells. Flow cytometry assay revealed that GRC-2 and prostratin inhibited cell cycle progression at the G2/M phase and induced apoptosis. The cytotoxic effect of GRC-2 and prostratin was accompanied by activation and nuclear translocation of PKC-δ and PKD as well as hyperactivation of extracellular signal-related kinase (ERK). Knockdown of either PKC-δ, PKD or ERK significantly protected A549 cancer cells from GRC-2- and prostratin-induced growth arrest as well as apoptosis. Taken together, our results have shown that prostratin and a more potent analogue GRC-2 reduce cell viability in NSCLC A549 cells, at least in part, through activation of the PKC-δ/PKD/ERK pathway, suggesting the potential of prostratin and GRC-2 as anticancer agents.
    • References:
      Semin Cancer Biol. 2018 Feb;48:18-26. (PMID: 28476658)
      Antiviral Res. 2018 Oct;158:63-77. (PMID: 30063970)
      Cancer Lett. 2015 Jan 28;356(2 Pt B):686-96. (PMID: 25449427)
      Anticancer Agents Med Chem. 2017;17(10):1304-1311. (PMID: 28270072)
      Mini Rev Med Chem. 2015;15(13):1122-30. (PMID: 25963564)
      Cancer Lett. 2006 Apr 8;235(1):1-10. (PMID: 15907369)
      Oncogene. 2004 Apr 22;23(19):3284-95. (PMID: 14981547)
      Elife. 2018 Nov 26;7:. (PMID: 30475204)
      Arch Immunol Ther Exp (Warsz). 2012 Oct;60(5):361-72. (PMID: 22918451)
      Semin Cancer Biol. 2018 Feb;48:36-52. (PMID: 28571764)
      Chem Rev. 2015 May 13;115(9):2975-3011. (PMID: 25906056)
      Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L429-38. (PMID: 10956616)
      Oncol Lett. 2018 Mar;15(3):3252-3258. (PMID: 29435066)
      Trends Pharmacol Sci. 2017 May;38(5):438-447. (PMID: 28283201)
      Planta Med. 1984 Feb;50(1):65-9. (PMID: 6739574)
      Oncogene. 2015 Apr 2;34(14):1758-67. (PMID: 24858045)
      J Nat Prod. 2016 Oct 28;79(10):2658-2666. (PMID: 27731641)
      EMBO Rep. 2011 Jul 08;12(8):785-96. (PMID: 21738220)
      Cancer Res. 1993 Jun 1;53(11):2507-12. (PMID: 8495413)
      J Biol Chem. 2011 Oct 14;286(41):35716-35724. (PMID: 21865164)
      J Biol Chem. 2007 Aug 3;282(31):22307-14. (PMID: 17562707)
      J Biol Chem. 2005 Sep 30;280(39):33262-9. (PMID: 16006559)
      J Biol Chem. 2003 Sep 5;278(36):33753-62. (PMID: 12824193)
      Kobe J Med Sci. 2006;52(6):181-94. (PMID: 17329956)
      Phytomedicine. 2019 Dec;65:153100. (PMID: 31648127)
      Exp Mol Med. 2004 Dec 31;36(6):557-62. (PMID: 15665589)
      J Biol Chem. 2005 Apr 8;280(14):13205-8. (PMID: 15701647)
      Trends Pharmacol Sci. 2006 Jun;27(6):317-23. (PMID: 16678913)
      J Biol Chem. 2004 Jul 2;279(27):28466-74. (PMID: 15123666)
      Chem Rev. 2014 Sep 10;114(17):8579-612. (PMID: 25036812)
      Biochim Biophys Acta Rev Cancer. 2017 Aug;1868(1):283-294. (PMID: 28577984)
    • Grant Information:
      MOST106-2320-B-037-003-MY3 Ministry of Science and Technology, Taiwan; KMU-TC108A03-4, KMU-DK109002~4 Kaohsiung Medical University; Grant 20391-3/2018/FEKUSTRAT Ministry of Human Capacities, Hungary
    • Contributed Indexing:
      Keywords: ERK; PKC-δ; PKD; phorbol ester; prostratin
    • Accession Number:
      0 (Carcinogens)
      0 (Phorbol Esters)
      EC 2.7.10.- (protein kinase D)
      EC 2.7.11.13 (Protein Kinase C)
      EC 2.7.11.13 (Protein Kinase C-delta)
      EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
    • Publication Date:
      Date Created: 20201017 Date Completed: 20210225 Latest Revision: 20240803
    • Publication Date:
      20240803
    • Accession Number:
      PMC7589005
    • Accession Number:
      10.3390/ijms21207579
    • Accession Number:
      33066446