Action mechanism of snake venom l-amino acid oxidase and its double-edged sword effect on cancer treatment: Role of pannexin 1-mediated interleukin-6 expression.

Autor: Truong NV; Institute of Bioinformatics and Structural Biology, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC., Phan TTT; Institute of Molecular and Cellular Biology, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC., Hsu TS; Institute of Molecular and Cellular Biology, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC., Phu Duc P; Institute of Bioinformatics and Structural Biology, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC., Lin LY; Institute of Molecular and Cellular Biology, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC. Electronic address: lylin@life.nthu.edu.tw., Wu WG; Institute of Bioinformatics and Structural Biology, College of Life Science, National Tsing Hua University, Hsinchu, 300044, Taiwan, ROC. Electronic address: wgwu@life.nthu.edu.tw.
Jazyk: angličtina
Zdroj: Redox biology [Redox Biol] 2023 Aug; Vol. 64, pp. 102791. Date of Electronic Publication: 2023 Jun 22.
DOI: 10.1016/j.redox.2023.102791
Abstrakt: Snake venom l-amino acid oxidases (svLAAOs) have been recognized as promising candidates for anticancer therapeutics. However, multiple aspects of their catalytic mechanism and the overall responses of cancer cells to these redox enzymes remain ambiguous. Here, we present an analysis of the phylogenetic relationships and active site-related residues among svLAAOs and reveal that the previously proposed critical catalytic residue His 223 is highly conserved in the viperid but not the elapid svLAAO clade. To gain further insight into the action mechanism of the elapid svLAAOs, we purify and characterize the structural, biochemical, and anticancer therapeutic potentials of the Thailand elapid snake Naja kaouthia LAAO (NK-LAAO). We find that NK-LAAO, with Ser 223, exhibits high catalytic activity toward hydrophobic l-amino acid substrates. Moreover, NK-LAAO induces substantial oxidative stress-mediated cytotoxicity with the magnitude relying on both the levels of extracellular hydrogen peroxide (H 2 O 2 ) and intracellular reactive oxygen species (ROS) generated during the enzymatic redox reactions, but not being influenced by the N-linked glycans on its surface. Unexpectedly, we discover a tolerant mechanism deployed by cancer cells to dampen the anticancer activities of NK-LAAO. NK-LAAO treatment amplifies interleukin (IL)-6 expression via the pannexin 1 (Panx1)-directed intracellular calcium (iCa 2+ ) signaling pathway to confer adaptive and aggressive phenotypes on cancer cells. Accordingly, IL-6 silencing renders cancer cells vulnerable to NK-LAAO-induced oxidative stress together with abrogating NK-LAAO-stimulated metastatic acquisition. Collectively, our study urges caution when using svLAAOs in cancer treatment and identifies the Panx1/iCa 2+ /IL-6 axis as a therapeutic target for improving the effectiveness of svLAAOs-based anticancer therapies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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