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

1
Graduate Institute of Natural Products, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
2
Department of Pharmacognosy, Interdisciplinary Excellence Centre, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
3
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7579; https://doi.org/10.3390/ijms21207579
Received: 23 September 2020 / Revised: 9 October 2020 / Accepted: 13 October 2020 / Published: 14 October 2020
(This article belongs to the Section Molecular Pharmacology)
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. View Full-Text
Keywords: prostratin; phorbol ester; PKC-δ; PKD; ERK prostratin; phorbol ester; PKC-δ; PKD; ERK
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MDPI and ACS Style

Tsai, J.-Y.; Rédei, D.; Hohmann, J.; Wu, C.-C. 12-Deoxyphorbol Esters Induce Growth Arrest and Apoptosis in Human Lung Cancer A549 Cells Via Activation of PKC-δ/PKD/ERK Signaling Pathway. Int. J. Mol. Sci. 2020, 21, 7579. https://doi.org/10.3390/ijms21207579

AMA Style

Tsai J-Y, Rédei D, Hohmann J, Wu C-C. 12-Deoxyphorbol Esters Induce Growth Arrest and Apoptosis in Human Lung Cancer A549 Cells Via Activation of PKC-δ/PKD/ERK Signaling Pathway. International Journal of Molecular Sciences. 2020; 21(20):7579. https://doi.org/10.3390/ijms21207579

Chicago/Turabian Style

Tsai, Ju-Ying, Dóra Rédei, Judit Hohmann, and Chin-Chung Wu. 2020. "12-Deoxyphorbol Esters Induce Growth Arrest and Apoptosis in Human Lung Cancer A549 Cells Via Activation of PKC-δ/PKD/ERK Signaling Pathway" International Journal of Molecular Sciences 21, no. 20: 7579. https://doi.org/10.3390/ijms21207579

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