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

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.

• Authors: Xiaoli Liu, Yan Gu, Yaoyao Bian, Danhong Cai, Yu Li, Ye Zhao, Zhaofeng Zhang, Mei Xue, Liang Zhang
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 26 Issue 3-4 Pg. 195-208 (04 2021) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 33550458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biological Products
• Biphenyl Compounds
• Lignans
• Reactive Oxygen Species
• honokiol
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Proteasome Endopeptidase Complex

Topics

• Apoptosis (drug effects)
• Biological Products (pharmacology)
• Biphenyl Compounds (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• In Vitro Techniques
• Leukemia, Promyelocytic, Acute (drug therapy, metabolism)
• Lignans (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Proteasome Endopeptidase Complex (drug effects)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (drug effects, metabolism)