Induction of an MLKL mediated non-canonical necroptosis through reactive oxygen species by tanshinol A in lung cancer cells.

Abstract

Recent discoveries revealed several types of programmed necrosis, such as necroptosis, ferroptosis, pyroptosis, etc. Necroptosis is mediated by signaling complexes with receptor-interacting protein kinases (RIPs) and mixed lineage kinase domain-like protein (MLKL). Here, we described an MLKL mediated non-canonical necroptosis through reactive oxygen species (ROS) in lung cancer cells triggered by a natural compound, tanshinol A (TSA). Morphologically, TSA-induced necrotic cell death is characterized by increased cell volume, transparent of cytoplasm, and rupture of the cell membrane. Biochemically, it induces intracellular ATP depletion and PI penetration. Molecularly, TSA-induced cell death is mediated by MLKL but independent of RIP1 and RIP3. Furthermore, TSA induces MLKL phosphorylation and membrane translocation, and cytosolic calcium accumulation. However, calcium shows no effect on TSA-induced cell death. Especially, TSA induces intracellular ROS generation, which was found to be the upstream of MLKL. Collectively, our data indicated that TSA triggers a novel type of programmed necrosis mediated by MLKL in lung cancer cells, which might have therapeutic potentials for lung cancer treatment.

• Authors: Xin Liu, Yiying Zhang, Hongwei Gao, Ying Hou, Jin-Jian Lu, Yulin Feng, Qiongming Xu, Bo Liu, Xiuping Chen
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 171 Pg. 113684 (01 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 31678492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Caffeic Acids
• Reactive Oxygen Species
• tanshinol
• MLKL protein, human
• Protein Kinases
• Calcium

Topics

• A549 Cells
• Apoptosis (drug effects)
• Caffeic Acids (pharmacology)
• Calcium (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Membrane (drug effects, metabolism)
• Cytosol (drug effects, metabolism)
• Enzyme Induction (drug effects)
• Humans
• Lung Neoplasms (metabolism, pathology)
• Necroptosis (drug effects)
• Phosphorylation (drug effects)
• Protein Kinases (biosynthesis)
• Reactive Oxygen Species (metabolism)