A novel 3′,5′-diprenylated chalcone induces concurrent apoptosis and GSDME-dependent pyroptosis through activating PKCδ/JNK signal in prostate cancer
A novel 3′,5′-diprenylated chalcone induces concurrent apoptosis and GSDME-dependent pyroptosis through activating PKCδ/JNK signal in prostate cancer
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新型 3',5'-二异戊二烯化查耳酮通过激活前列腺癌中的 PKC delta/JNK 信号诱导同时发生细胞凋亡和 GSDME 依赖性细胞焦亡
DOI：
10.18632/aging.103178
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发表时间：
2020-05-31
期刊：
影响因子：
5.2
通讯作者：
Zhu, Jianguo
中科院分区：
文献类型：
--
作者：
Zhang, Yongqiang;Yang, Jue;Zhu, Jianguo
虽然雄激素剥夺疗法最初可能对前列腺癌有效，但该疾病可逐渐进展为去势抵抗性前列腺癌，此时化疗成为主要的临床策略。在这项研究中，我们证明了一种新的3 '，5'-二异戊二烯化查耳酮（C10）的抗癌潜力，它在体外和体内选择性地抑制PC 3细胞的增殖。C10处理增加了PC 3细胞在亚G1期的比例，并诱导细胞程序性死亡。有趣的是，C10引起并发的半胱天冬酶依赖性凋亡和gasdermin E依赖性pyropottic事件。RNA-Seq和生物信息学分析揭示了前列腺癌中蛋白激酶C δ（PKC δ）和丝裂原活化蛋白激酶途径活化之间的强相关性。PC 3细胞中的PKC δ沉默抑制JNK通路的激活及其下游基因的表达，包括Bax、白细胞介素-6和白细胞介素-1 β，其参与凋亡和pyroptotic过程。此外，在PC 3细胞异种移植肿瘤组织中，C10处理抑制肿瘤生长并上调PKC δ。这些发现表明，C10处理诱导PKC δ/JNK通路，从而激活Caspase-3并诱导PARP和gasdermin E裂解，以在前列腺癌细胞中执行凋亡和细胞裂解性热凋亡。
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 (PKC delta) and mitogen-activated protein kinase pathway activation in prostate cancer. PKC delta silencing in PC3 cells suppressed the activation of the JNK pathway and the expression of its downstream genes, including Bax, interleukin-6 and interleukin-1 beta, which are involved in apoptotic and pyroptotic processes. Moreover, in PC3 cell xenograft tumor tissues, C10 treatment inhibited tumor growth and upregulated PKC delta. These findings suggest that C10 treatment induces the PKC delta/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.