Dataset Information

Oridonin induces autophagy-mediated cell death in pancreatic cancer by activating the c-Jun N-terminal kinase pathway and inhibiting phosphoinositide 3-kinase signaling.

ABSTRACT:

Background

Oridonin is a diterpenoid isolated from Rabdosia rubescens that has potent anticancer activity. This study set out to investigate the antitumor effects of oridonin in pancreatic carcinoma (PC) and their underlying mechanisms.

Methods

To investigate the antitumor effects of oridonin, we developed an orthotopic C57BL/6 mouse model of PC. After successful establishment of the model, the mice were given a daily intraperitoneal injection of phosphate-buffered saline containing 0.1% dimethyl sulfoxide or oridonin for 2 weeks. In vitro experiments including MTT assay and flow cytometry were performed to examine cell viability and apoptosis. Panc-1 and Panc02 cells were transfected with a green fluorescent protein (GFP)-LC3 plasmid. After the cells had been treated with or without 20 μM oridonin and 10 μM 3-MA, the formation of GFP-LC3 puncta was detected by fluorescence microscopy. The levels of the autophagy-related proteins Beclin-1, LC3, and p62 were measured by western blotting.

Results

Oridonin inhibited the proliferation of PC cells and induced their apoptosis in vitro and in vivo. Treatment with oridonin also led to an increase in the quantity of LC3B II protein and upregulation of the p62 and Beclin-1 levels in PC cells. The effects of oridonin on PC cell proliferation, apoptosis, and autophagy were mediated via the simultaneous inhibition of the phosphoinositide 3-kinase pathway and activation of the c-Jun N-terminal kinase pathway.

Conclusions

Our study is the first to confirm the antitumor and autophagy-activating effects of oridonin on PC cells. In light of these results, oridonin may be a promising therapeutic agent for PC.

SUBMITTER: Zhao X

PROVIDER: S-EPMC8339817 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Oridonin induces autophagy-mediated cell death in pancreatic cancer by activating the c-Jun N-terminal kinase pathway and inhibiting phosphoinositide 3-kinase signaling.

Zhao Xin X Zhang Qi Q Wang Yuanyuan Y Li Shipeng S Yu Xiangyang X Wang Botao B Wang Ximo X

Annals of translational medicine 20210701 13

<h4>Background</h4>Oridonin is a diterpenoid isolated from <i>Rabdosia rubescens</i> that has potent anticancer activity. This study set out to investigate the antitumor effects of oridonin in pancreatic carcinoma (PC) and their underlying mechanisms.<h4>Methods</h4>To investigate the antitumor effects of oridonin, we developed an orthotopic C57BL/6 mouse model of PC. After successful establishment of the model, the mice were given a daily intraperitoneal injection of phosphate-buffered saline c ...[more]

PMID: 34422996

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Project description:Background and purpose2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although the cytotoxic efficacy of RH1 against tumours has been studied extensively, the molecular mechanisms underlying this anti-cancer activity have not yet been fully elucidated.Experimental approach2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone-induced apoptosis and related signalling pathways in NQO1-negative and NQO1-overexpressing cells were evaluated. The role of p53 in RH1-induced cell death was investigated using parental and p53-deficient RKO human colorectal cancer cells by assaying clonogenic cell survival. Specific inhibitors and siRNAs targeting factors involved in RH1-induced apoptosis were used to clarify the roles played by such factors in RH1-activated apoptotic signalling pathways.Key results2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone induced apoptosis and clonogenic death, dependent on NQO1 and p53. Treatment of NQO1-overexpressing cells with RH1 caused rapid disruption of mitochondrial membrane potential, nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G) from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNA targeting AIF and Endo G effectively attenuated RH1-induced apoptotic cell death. Moreover, RH1 induced cleavage of Bax, which targets mitochondria. RH1 significantly activated the c-Jun N-terminal kinase (JNK) pathway, and inhibition of this pathway suppressed RH1-induced mitochondria-mediated apoptosis. RH1-induced generation and mitochondrial translocation of cleaved Bax were blocked by the JNK inhibitor, SP600125. Inhibition of JNK with SP600125 attenuated the mitochondrial translocation of JNK.Conclusions and implications2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone activated JNK, resulting in mitochondria-mediated apoptotic cell death that was NQO1-dependent.

Dataset Information

Oridonin induces autophagy-mediated cell death in pancreatic cancer by activating the c-Jun N-terminal kinase pathway and inhibiting phosphoinositide 3-kinase signaling.

Background

Methods

Results

Conclusions

Publications

Oridonin induces autophagy-mediated cell death in pancreatic cancer by activating the c-Jun N-terminal kinase pathway and inhibiting phosphoinositide 3-kinase signaling.

Similar Datasets

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