Research Paper Volume 12, Issue 10 pp 9103—9124
A novel 3’,5’-diprenylated chalcone induces concurrent apoptosis and GSDME-dependent pyroptosis through activating PKCδ/JNK signal in prostate cancer
- 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, P.R. China
- 2 Guizhou Provincial People’s Hospital, Guiyang 550002, P.R. China
- 3 Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, P.R. China
Received: October 7, 2019 Accepted: April 16, 2020 Published: May 19, 2020https://doi.org/10.18632/aging.103178
How to Cite
Copyright © 2020 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Although androgen deprivation therapy may initially be effective in prostate cancer, the disease can gradually progress to castration-resistant prostate cancer, at which point chemotherapy becomes the major clinical strategy. In this study, we demonstrated the anti-cancer potential of a novel 3’,5’-diprenylated chalcone (C10), which selectively inhibited the proliferation of PC3 cells in vitro and in vivo. C10 treatment elevated the proportion of PC3 cells in sub-G1 phase and induced programmed cell death. Interestingly, C10 elicited concurrent Caspase-dependent apoptotic and gasdermin E-dependent pyroptotic events. RNA-Seq and bioinformatics analyses revealed a strong correlation between protein kinase C delta (PKCδ) and mitogen-activated protein kinase pathway activation in prostate cancer. PKCδ silencing in PC3 cells suppressed the activation of the JNK pathway and the expression of its downstream genes, including Bax, interleukin-6 and interleukin-1β, which are involved in apoptotic and pyroptotic processes. Moreover, in PC3 cell xenograft tumor tissues, C10 treatment inhibited tumor growth and upregulated PKCδ. These findings suggest that C10 treatment induces the PKCδ/JNK pathway, thereby activating Caspase-3 and inducing the cleavage of PARP and gasdermin E to execute apoptosis and cell-lytic pyroptosis in prostate cancer cells.
C10: 3’,5’-diprenylated chalcone; DAPI: 4',6-diamidino-2-phenylindole; FITC: fluorescein isothiocyanate; GSDMD/E: gasdermin D/E; IL: interleukin; KEGG: Kyoto Encyclopedia of Genes and Genomes; LDH: lactate dehydrogenase; MAPK: mitogen-activated protein kinase; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide; NF-κB: nuclear factor kappa B; NLRP3: NLR pyrin domain containing 3; PCa: prostate cancer; PCD: programmed cell death; PCNA: proliferating cell nuclear antigen; PI: propidium iodide; PKC: protein kinase C; PPI: protein-protein interaction.