Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-22235-8
Keywords
-
Categories
Funding
- China National Natural Science Foundation [81973710, 81673544, 81974469, 81672635, 81903107, 21472247]
- Hunan Provincial Key Program for Research and Development [2018SK21310, 2018SK21214]
- Outstanding Youth Foundation of Hunan Provincial Department of Education [20B589]
- Scientific Research Project of Hunan Provincial Health and Family Planning Commission [C2016125]
- postgraduate innovation project of Central South University of China [2016zzts167]
Ask authors/readers for more resources
ASS1 acts as a tumor suppressor in breast cancer, and SPA and LM-2I can suppress breast tumor cell proliferation and growth by activating ASS1. Treatment with SPA and LM-2I significantly enhances ASS1 enzymatic activity in breast cancer cells, especially those with low ASS1 expression, leading to reduced pyrimidine synthesis and inhibition of cancer cell proliferation.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available