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

Xin Zhao; Qi Zhang; Yuanyuan Wang; Shipeng Li; Xiangyang Yu; Botao Wang; Ximo Wang

doi:10.21037/atm-21-2630

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

Ann Transl Med. 2021 Jul;9(13):1084. doi: 10.21037/atm-21-2630.

Authors

Xin Zhao^{1

2}, Qi Zhang², Yuanyuan Wang³, Shipeng Li⁴, Xiangyang Yu⁵, Botao Wang^{2

6}, Ximo Wang²

Affiliations

¹ Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
² Tianjin Key Laboratory for Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China.
³ Department of Pharmacology, Tianjin Children's Hospital, Tianjin, China.
⁴ Department of General Surgery, Jiaozuo People's Hospital, Xinxiang Medical University, Jiaozuo, China.
⁵ Department of Gastrointestinal Surgery, Tianjin Nankai Hospital, Tianjin, China.
⁶ Tianjin Medical University, Tianjin, China.

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.

Keywords: LC3; Oridonin; apoptosis; autophagy; pancreatic carcinoma.