2. Academic Validation
  3. N-Methylparoxetine Blocked Autophagic Flux and Induced Apoptosis by Activating ROS-MAPK Pathway in Non-Small Cell Lung Cancer Cells

N-Methylparoxetine Blocked Autophagic Flux and Induced Apoptosis by Activating ROS-MAPK Pathway in Non-Small Cell Lung Cancer Cells

  • Int J Mol Sci. 2019 Jul 11;20(14):3415. doi: 10.3390/ijms20143415.
Kun Wang 1 2,  Bonan Chen 1 3,  Ting Yin 1 3,  Yujuan Zhan 3,  Yuhua Lu 2,  Yilin Zhang 2,  Jiawei Chen 3,  Weijie Wu 3,  Shikun Zhou 3,  Wenli Mao 1 2,  Yuhui Tan 3,  Biaoyan Du 2,  Xiaodong Liu 4,  Hiuting Idy Ho 5,  Jianyong Xiao 6 7
Affiliations

Affiliations

  • 1 Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 2 Department of Pathology, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 3 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 4 Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
  • 5 Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR 999077, China. b144156@cuhk.edu.hk.
  • 6 Research Center of Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. jianyongxiao@gzucm.edu.cn.
  • 7 Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. jianyongxiao@gzucm.edu.cn.
PMID: 31336784 DOI: 10.3390/ijms20143415
Abstract

The main mechanistic function of most chemotherapeutic drugs is mediated by inducing mitochondria-dependent Apoptosis. Tumor cells usually respond to upregulate Autophagy to eliminate impaired mitochondria for survival. Hypothetically, inhibiting Autophagy might promote mitochondria-dependent Apoptosis, thus enhancing the efficacy of chemotherapeutic therapies. We previously identified N-methylparoxetine (NMP) as an inducer of mitochondrial fragmentation with subsequent Apoptosis in non-small cell lung Cancer (NSCLC) cells. We discovered that ROS was accumulated in NMP-treated NSCLC cells, followed by c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38) activation. This was reversed by the application of a Reactive Oxygen Species (ROS) scavenger, N-acetylcysteine (NAC), leading to a reduction in Apoptosis. Our data suggested that NMP induced Apoptosis in NSCLC cells by activating mitogen-activated protein kinase (MAPK) pathway. We further speculated that the remarkable increase of ROS in NMP-treated NSCLC cells might result from an inhibition of Autophagy. Our current data confirmed that NMP blocked Autophagy flux at late stage wherein lysosomal acidification was inhibited. Taken together, this study demonstrated that NMP could exert dual apoptotic functions-mitochondria impairment and, concomitantly, Autophagy inhibition. NMP-related excessive ROS accumulation induced Apoptosis by activating the MAPK pathway in NSCLC cells.

Keywords

MAPK; N-Methylparoxetine; NSCLC; ROS; apoptosis; autophagy inhibition.

Figures
Products