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

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.

Silencing FYVE, RhoGEF, and PH domain containing 1 (FGD1) suppresses melanoma progression by inhibiting PI3K/AKT signaling pathway

“…Then, tissues had been cultivated with 3,3‐Diaminobenzidine (DAB) for 1 minute and counterstained with hematoxylin. For hematoxylin and eosin (HE) staining [ 19 ], lung tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections at 5 µm thickness were stained with hematoxylin and eosin solution followed by dehydration with graded alcohol and clearing in xylene.…”

Argininosuccinate synthase 1, arginine deprivation therapy and cancer management

“…It has been demonstrated that spinosyn A and its derivative LM-2I exhibit anti-tumor function, which is regulated by activation of ASS1. Mechanistically, spinosyn A binds to ASS1 at the 97th cysteine site in tumor cells, thus increasing ASS1 enzymatic activity and anti-tumor effect (Zou et al, 2021). Currently, the investigation on the development of ASS1 activators is still limited, it is still required to explore deeper to identify the safety and efficacy of ASS1 activators.…”

PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway

“…ASS1 is known as the rate-limiting enzyme in arginine metabolism [28]. Notably, recent studies deepened our insights into the role of ASS1 as a novel tumor suppressive character [17,29]. Thus, we were urged to explore the biological association of PGAM1 and ASS1.…”

“…Nevertheless, most treatment strategies for ASS1-deficient tumors neglect the tumor-suppressive effect of ASS1. Actually, the method of reconstructing the activity or expression of ASS1 in cancer cells is particularly important for tumor therapy [17]. In BC, Zou et al [17] discovered that spinosyn A and its derivatives significantly inhibit tumor growth by activation of ASS1.…”

“…Actually, the method of reconstructing the activity or expression of ASS1 in cancer cells is particularly important for tumor therapy [17]. In BC, Zou et al [17] discovered that spinosyn A and its derivatives significantly inhibit tumor growth by activation of ASS1. In HCC, treatment with decitabine could increase ASS1 expression, thereby facilitating the robust therapeutic activity of combined decitabine and anti-HCC therapies like cisplatin [18].…”