一种新发现的直翅目甲由α-d-葡聚糖作为醛缩酶 A 的选择性抑制剂的抗肿瘤作用。

The antitumor role of a newly discovered α-d-glucan from Holotrichia diomphalia Bates as a selective blocker of aldolase A.

机构信息

Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, China.

Department of Pharmacology and Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, China; School of Pharmacy, Xi'an Medical University, Xi'an, China.

出版信息

Carbohydr Polym. 2021 Mar 1;255:117532. doi: 10.1016/j.carbpol.2020.117532. Epub 2020 Dec 18.

DOI:10.1016/j.carbpol.2020.117532

PMID:33436261

Abstract

Aldolase A (ALDOA) facilitated aerobic glycolysis in cancer cells is a potential target in the treatment of hepatocellular carcinoma (HCC). However, only few effective inhibitors of ALDOA have been reported until now. In this research, we found a polysaccharide called HDPS-4II from Holotrichia diomphalia Bates, which can specifically bind to ALDOA with a dissociation constant of 2.86 μM. HDPS-4II with a molecular weight of 19 kDa was a linear triple-helix glucan composed of ɑ-d-1,4-Glcp and ɑ-d-1,6-Glcp in a ratio of 1.0:10.0. HDPS-4II significantly inhibited aldolase enzyme activity, glycolysis, and further inhibited the expression of phosphorylated AMPKα in HCC cells. Through analyzing ALDOA-overexpressing and -knockdown cells, it was confirmed that ALDOA mediated the viability and glycolysis inhibition of HDPS-4II. Moreover, HDPS-4II administration markedly inhibited tumor growth in mice xenografted with HCCs. These findings suggest that HDPS-4II, as an ALDOA antagonist, is a promising remedy in the treatment and prevention of HCC.

摘要

醛缩酶 A（ALDOA）促进癌细胞的有氧糖酵解，是治疗肝细胞癌（HCC）的潜在靶点。然而，到目前为止，只报道了少数有效的 ALDOA 抑制剂。在这项研究中，我们发现了一种来自暗黑鳃金龟 Holotrichia diomphalia Bates 的多糖，称为 HDPS-4II，它可以与 ALDOA 特异性结合，解离常数为 2.86 μM。分子量为 19 kDa 的 HDPS-4II 是一种由α-d-1,4-Glcp 和α-d-1,6-Glcp 以 1.0:10.0 的比例组成的线性三聚体葡聚糖。HDPS-4II 显著抑制醛缩酶酶活性、糖酵解，并进一步抑制 HCC 细胞中磷酸化 AMPKα 的表达。通过分析过表达和敲低 ALDOA 的细胞，证实 ALDOA 介导了 HDPS-4II 对细胞活力和糖酵解的抑制作用。此外，HDPS-4II 给药显著抑制了 HCC 荷瘤小鼠的肿瘤生长。这些发现表明，作为 ALDOA 拮抗剂的 HDPS-4II 是治疗和预防 HCC 的一种很有前途的方法。