Ganoderma lucidum (G. lucidum) extracts, as dietary supplements, have been found to exert potent anticancer activity, which is attributed to the presence of polysaccharides and triterpenes. However, the molecular mechanism underlying the anticancer action of G. lucidum extracts remains to be investigated. Here, we show that ReishiMax GLp, containing G. lucidum polysaccharides and triterpenes (GLPT), inhibited cell proliferation and induced cell death in human lung cancer cells (A549 and A427) and simultaneously suppressed the signaling pathways of mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2), respectively. Mechanistically, GLPT downregulated the phosphorylation and protein levels of insulin-like growth factor 1 receptor (IGFR) and phosphoinositide 3-kinase (PI3K) as well as the protein level of RAS homolog enriched in brain (Rheb). In addition, GLPT also activated the AMP-activated protein kinase (AMPK) network. This was evidenced by observations that GLPT increased the phosphorylation of AMPKα (T172) and its substrates tuberous sclerosis complex 2 (TSC2, S1387) and regulatory-associated protein of mTOR (raptor, S792). Ectopic expression of dominant-negative AMPKα partially mitigated the inhibitory effect of GLPT on mTORC1, indicating that GLPT inhibits mTORC1 partly by activating AMPK. The results suggest that G. lucidum extracts exert anticancer action at least partly by suppressing mTORC1/2 signaling via activation of AMPK and inhibition of IGFR/PI3K/Rheb in tumor cells.

灵芝（G. lucidum）提取物作为膳食补充剂，被发现具有有效的抗癌活性，这归因于多糖和三萜的存在。然而，灵芝提取物抗癌作用的分子机制仍有待研究。在这里，我们发现含有灵芝多糖和三萜（GLPT）的ReishiMax GLp能够抑制人肺癌细胞（A549和A427）的细胞增殖并诱导细胞死亡，同时抑制哺乳动物雷帕霉素复合物1和1的靶标信号通路。 2（mTORC1 和 mTORC2），分别。从机制上讲，GLPT 下调胰岛素样生长因子 1 受体 (IGFR) 和磷酸肌醇 3-激酶 (PI3K) 的磷酸化和蛋白质水平，以及大脑中富集的 RAS 同源物 (Rheb) 的蛋白质水平。此外，GLPT还激活AMP激活蛋白激酶（AMPK）网络。GLPT 增加了 AMPKα (T172) 及其底物结节性硬化症复合体 2 (TSC2, S1387) 和 mTOR (raptor, S792) 调节相关蛋白的磷酸化，证明了这一点。显性失活 AMPKα 的异位表达部分减轻了 GLPT 对 mTORC1 的抑制作用，表明 GLPT 部分通过激活 AMPK 抑制 mTORC1。结果表明，灵芝提取物至少部分通过激活 AMPK 和抑制肿瘤细胞中的 IGFR/PI3K/Rheb 来抑制 mTORC1/2 信号传导，从而发挥抗癌作用。