14-Deoxycoleon U-induced endoplasmic reticulum stress-mediated apoptosis, autophagy, and cell cycle arrest in lung adenocarcinoma

Abstract

Xiaozhi Peng,*,1 Yijun Tu,*,1 San Fu,2 Yu Xia,1 Chaozhi Ma,1 Yanfang Yang,1 Hezhen Wu,3 Yanwen Liu,1 Pengtao You11Hubei Key Laboratory of Resources and Chemistry of Chinese Medicine, Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, 430065, People’s Republic of China; 2State Key Laboratory of Natural Medicines, Research Department of Pharmacognosy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China; 3Department of Pharmacy, College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, 430065, People’s Republic of China*These authors contributed equally to this workObjective: 14-Deoxycoleon U is a natural abietane-type diterpene and exerts an inhibitory effect on tumor cells proliferation, which suggests that 14-Deoxycoleon U may be a potent anti-cancerous lead compound for lung cancer treatment. This study was to evaluate potential of 14-Deoxycoleon U to treat lung adenocarcinoma in vitro and in vivo.Methods: In the present study, the cell viability and apoptosis morphology of 14-Deoxycoleon U-treated A549 and LLC cells were explored using cell counting kit-8 assay and Hoechst 33258 staining. Then, the protein expressions about apoptosis, endoplasmic reticulum (ER) stress, autophagy and cell cycle were measured using Western blot. The autophagosome formation of 14-Deoxycoleon U-treated A549 cells was visualized using a confocal microscopy. LLC lung adenocarcinoma model was established.Results: The results indicated that 14-Deoxycoleon U significantly inhibited A549 and LLC cell proliferation in a dose-dependent manner via caspase-dependent apoptosis. Furthermore, apoptosis of both cells was mediated by 14-Deoxycoleon U-induced ER stress. In addition, 14-Deoxycoleon U-induced A549 and LLC cell autophagy, thus promoting their death. Moreover, 14-Deoxycoleon U-induced cell cycle arrest in both cells via inhibition of cyclin D3, cyclin-dependent kinase 6, CDC2 and up-regulation of p21. In vivo results showed that administration of 14-Deoxycoleon U significantly suppressed LLC growth and adverse effects of 14-Deoxycoleon U on organs might be lower than of adriamycin.Conclusion: Overall, our results demonstrated that 14-Deoxycoleon U represses in vitro and in vivo growth of lung adenocarcinoma through ER stress-mediated apoptosis accompanied by autophagy and cell cycle arrest.Keywords: 14-Deoxycoleon U, apoptosis, endoplasmic reticulum, autophagy, cell cycle

Keywords

• 14-Deoxycoleon U
• apoptosis
• endoplasmic reticulum
• autophagy
• cell cycle