2. Academic Validation
  3. Suppression of JNK/ERK dependent autophagy enhances Jaspine B derivative-induced gastric cancer cell death via attenuation of p62/Keap1/Nrf2 pathways

Suppression of JNK/ERK dependent autophagy enhances Jaspine B derivative-induced gastric cancer cell death via attenuation of p62/Keap1/Nrf2 pathways

  • Toxicol Appl Pharmacol. 2022 Mar 1;438:115908. doi: 10.1016/j.taap.2022.115908.
Feng Xu 1,  Qin Xie 2,  Ya-Wei Li 2,  Qing-Qing Jing 2,  Xiao-Jie Liu 2,  Yi-Chao Xu 3,  Xu Wang 2,  Lu Liu 2,  GiYoung Kim 4,  YungHyun Choi 5,  Yong Guo 6,  En Zhang 7,  Cheng-Yun Jin 8
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 2 Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.
  • 3 Key Laboratory of Advanced Technology for Drug Preparation, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China.
  • 4 Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
  • 5 Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea.
  • 6 Key Laboratory of Advanced Technology for Drug Preparation, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China. Electronic address: guoyong-122@163.com.
  • 7 Key Laboratory of Advanced Technology for Drug Preparation, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China. Electronic address: zhangen@zzu.edu.cn.
  • 8 Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; Key Laboratory of Advanced Technology for Drug Preparation, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province 450052, China. Electronic address: cyjin@zzu.edu.cn.
PMID: 35123989 DOI: 10.1016/j.taap.2022.115908
Abstract

Gastric Cancer is one of the most common cancers with few effective treatments, a new treatment agent is desperately needed. C-2, a Jaspine B derivative, has shown anti-cancer efficacy in gastric Cancer cells. The anti-cancer mechanism, however, remains unknown. As a result, we investigate the anti-cancer effect and the underlying mechanism of C-2 in gastric Cancer cells. The results showed that C-2 selectively reduced the proliferation of gastric Cancer cells when compared to normal epithelial gastric cells. Western blotting and flow cytometry further demonstrated that Caspase9 is involved in causing cell death. Meanwhile, C-2 triggered Autophagy in gastric Cancer cells, inhibition of which with LY294002 can enhance the anti-proliferative activity of C-2. Next, we found that C-2 triggered Autophagy through activating JNK/ERK, and that inhibitors of these proteins exacerbated C-2 induced cell death. Mechanically, enhanced phosphorylation of JNK/ERK elevated Beclin-1 by disturbing Beclin-1/Bcl-xL or Beclin-1/Bcl-2 complexes, resulting in Autophagy and up-regulation of p62. Finally, p62 binds Keap1 competitively to release Nrf2, boosting Nrf2 translocation from the cytoplasm to the nucleus and triggering expression of Nrf2 target genes, so enhancing survival. C-2 inhibited the growth of gastric Cancer cells, while JNK/ERK dependent Autophagy antagonized C-2 induced cell growth inhibition through p62/Keap1/Nrf2 pathway.

Keywords

Autophagy; Gastric cancer cells; JNK/ERK; Jaspine B derivative; p62/Keap1/Nrf2.

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