Naturally-occurring spinosyn A and its derivatives function as argininosuccinate synthase activator and tumor inhibitor

Zizheng Zou, Xiyuan Hu, Tiao Luo, Zhengnan Ming, Xiaodan Chen, Li Xia, Wensong Luo, Jijia Li, Na Xu, Ling Chen, Dongsheng Cao, Min Wen, Fanrong Kong, Kunjian Peng, Yuanzhu Xie, Xuan Li, Dayou Ma, Chuanyu Yang, Ceshi Chen, Wenjun Yi, Ousheng Liu, Suyou Liu (), Junli Luo () and Zhiyong Luo ()
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Zizheng Zou: Central South University
Xiyuan Hu: Central South University
Tiao Luo: Central South University
Zhengnan Ming: Central South University
Xiaodan Chen: Central South University
Li Xia: Shanghai Jiao Tong University School of Medicine
Wensong Luo: Central South University
Jijia Li: Central South University
Na Xu: Central South University
Ling Chen: Central South University
Dongsheng Cao: Central South University
Min Wen: Central South University
Fanrong Kong: Central South University
Kunjian Peng: Central South University
Yuanzhu Xie: Central South University
Xuan Li: Central South University
Dayou Ma: Central South University
Chuanyu Yang: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences
Ceshi Chen: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences
Wenjun Yi: Central South University
Ousheng Liu: Central South University
Suyou Liu: Central South University
Junli Luo: Central South University
Zhiyong Luo: Central South University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.

Date: 2021
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DOI: 10.1038/s41467-021-22235-8

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