Department of Plastic Surgery, Zhongnan Hospital of Wuhan University; College of Chemistry and Molecular Sciences; Hubei Engineering Center of Natural Polymer-Based Medical Materials; Wuhan University, Wuhan 430072, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China.
Int J Biol Macromol. 2024 Nov;281(Pt 2):136309. doi: 10.1016/j.ijbiomac.2024.136309. Epub 2024 Oct 5.
Lentinus β-D-glucan (LNT), derived from artificially cultured mushrooms of Lentinus edodes, shows an important yet incompletely understood biological functions in cancer. In this work, the chemical structure of the refined LNT comprising a β-D-(1, 6)-branched β-D-(1,3)-glucan was further clarified via 1D- and 2D-NMR with high resolution, and its drug resistance resulted from autophagy in human cervical cancer (CC) Hela cells besides its anti-cancer function were revealed in vitro and in vivo. In detail, LNT destroyed cellular homeostasis by significantly increasing the intracellular Ca levels and promoted autophagic flux in vitro Hela cells, which was found to at least partially depend on the PI3K/Akt/mTOR-mediated pathway by up-regulating LC3-II levels and down-regulating the expression of p62, PI3K, p-Akt, and mTOR in Hela cells-transplanted BALB/c nude mice. In particular, LNT-induced autophagy led to a drug resistance against LNT-induced proliferation inhibition and apoptosis in Hela cells, and the co-treatment of autophagy inhibitors and LNT significantly enhanced the inhibition of Hela cells and tumor growth in vitro and in vivo. Therefore, the combination of LNT and autophagy inhibitors will be a novel therapeutic strategy to reduce the resistance and improve the prognosis of CC patients in the clinical.
香菇β-D-葡聚糖（LNT）来源于人工培养的香菇，在癌症中具有重要但尚未完全了解的生物学功能。在这项工作中，通过高分辨率的 1D 和 2D-NMR 进一步阐明了精制 LNT 的化学结构，由β-D-（1,6）-支链β-D-（1,3）-葡聚糖组成，其在体外和体内均揭示了除抗癌作用外，其在人宫颈癌（CC）Hela 细胞中还具有抗药性，源于自噬。具体而言，LNT 通过显著增加细胞内 Ca 水平破坏细胞内稳态，并促进体外 Hela 细胞中的自噬流，这至少部分取决于通过上调 LC3-II 水平和下调 p62、PI3K、p-Akt 和 mTOR 的表达来抑制 PI3K/Akt/mTOR 介导的途径在 Hela 细胞-移植 BALB/c 裸鼠中。特别是，LNT 诱导的自噬导致 Hela 细胞对 LNT 诱导的增殖抑制和凋亡的耐药性，自噬抑制剂和 LNT 的联合处理显著增强了体外和体内对 Hela 细胞和肿瘤生长的抑制作用。因此，LNT 和自噬抑制剂的联合应用将是一种减少耐药性和改善 CC 患者临床预后的新治疗策略。
