Shen Xinyi, Jain Abhishek, Aladelokun Oladimeji, Yan Hong, Gilbride Austin, Ferrucci Leah M, Lu Lingeng, Khan Sajid A, Johnson Caroline H
Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, United States.
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, United States.
Front Mol Biosci. 2022 Aug 25;9:958666. doi: 10.3389/fmolb.2022.958666. eCollection 2022.
Asparagine (Asn) and enzymes that catalyze the metabolism of Asn have been linked to the regulation and propagation of colorectal cancer (CRC). Increased Asn and asparagine synthetase (ASNS) expression, both contribute to CRC progression and metastasis. In contradistinction, L-asparaginase (ASNase) which breaks down Asn, exhibits an anti-tumor effect. Metabolic pathways such as KRAS/PI3K/AKT/mTORC1 signaling and high SOX12 expression can positively regulate endogenous Asn production. Conversely, the tumor suppressor, TP53, negatively impacts ASNS, thus limiting Asn synthesis and reducing tumor burden. Asn abundance can be altered by factors extrinsic to the cancer cell such as diet, the microbiome, and therapeutic use of ASNase. Recent studies have shown that sex-related factors can also influence the regulation of Asn, and high Asn production results in poorer prognosis for female CRC patients but not males. In this narrative review, we critically review studies that have examined endogenous and exogenous modulators of Asn bioavailability and summarize the key metabolic networks that regulate Asn metabolism. We also provide new hypotheses regarding sex-related influences on Asn, including the involvement of the sex-steroid hormone estrogen and estrogen receptors. Further, we hypothesize that sex-specific factors that influence Asn metabolism can influence clinical outcomes in CRC patients.
天冬酰胺（Asn）以及催化Asn代谢的酶与结直肠癌（CRC）的调控和扩散有关。Asn和天冬酰胺合成酶（ASNS）表达增加均会促进CRC的进展和转移。相反，分解Asn的L-天冬酰胺酶（ASNase）具有抗肿瘤作用。诸如KRAS/PI3K/AKT/mTORC1信号传导和高SOX12表达等代谢途径可正向调节内源性Asn的产生。相反，肿瘤抑制因子TP53对ASNS产生负面影响，从而限制Asn的合成并减轻肿瘤负担。Asn的丰度可受癌细胞外部因素的影响，如饮食、微生物群和ASNase的治疗应用。最近的研究表明，性别相关因素也可影响Asn的调节，Asn产量高会导致女性CRC患者预后较差，而男性则不然。在这篇叙述性综述中，我们批判性地回顾了研究Asn生物利用度的内源性和外源性调节因子的研究，并总结了调节Asn代谢的关键代谢网络。我们还提出了关于性别对Asn影响的新假设，包括性甾体激素雌激素和雌激素受体的参与。此外，我们假设影响Asn代谢的性别特异性因素可影响CRC患者临床结局。
