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Honokiol induces paraptosis - like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

Authors
  • Liu, Xiaoli1
  • Gu, Yan2
  • Bian, Yaoyao1
  • Cai, Danhong1
  • Li, Yu1
  • Zhao, Ye1
  • Zhang, Zhaofeng1
  • Xue, Mei1
  • Zhang, Liang1
  • 1 Nanjing University of Chinese Medicine,
  • 2 Department of Geriatrics, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210003 People’s Republic of China
Type
Published Article
Journal
APOPTOSIS
Publisher
Springer-Verlag
Publication Date
Feb 07, 2021
Volume
26
Issue
3
Pages
195–208
Identifiers
DOI: 10.1007/s10495-020-01655-9
PMID: 33550458
PMCID: PMC8016806
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

Acute promyelocytic leukemia (APL) is a blood system disease caused by the accumulation of a large number of immature blood cells in bone marrow. Although the introduction of all- trans retinoic acid (ATRA) and arsenic has reached a high level of complete remission rate and 5-year disease-free survival rate, the occurrence of various adverse reactions still severely affects the quality of life of patients. As a natural product, honokiol (HNK) has the advantages of low toxicity and high efficiency, and it is a potential drug for the treatment of cancer. Since cancer cells can escape apoptotic cell death through multiple adaptive mechanisms, HNK, a drug that induces cancer cell death in a nonapoptotic way, has attracted much interest. We found that HNK reduced the viability of human APL cell line (NB4 cells) by inducing paraptosis-like cell death. The process was accompanied by excessive reactive oxygen species (ROS), mitochondrial damage, endoplasmic reticulum stress, and increased microtubule-associated protein 1 light chain 3 (LC3) processing. The inactivation of proteasome activity was the main cause of misfolded and unfolded protein accumulation in endoplasmic reticulum, such as LC3II/I and p62. This phenomenon could be alleviated by adding cycloheximide (CHX), a protein synthesis inhibitor. We found that mTOR signaling pathway participated in paraptosis-like cell death induced by HNK in an autophagy-independent process. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway induced paraptosis of NB4 cells by promoting endoplasmic reticulum stress. In summary, these findings indicate that paraptosis may be a new way to treat APL, and provide novel insights into the potential mechanism of paraptosis-like cell death. Supplementary Information The online version of this article (10.1007/s10495-020-01655-9) contains supplementary material, which is available to authorized users.

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