Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai 200235, China.
Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province 212001, China.
J Ethnopharmacol. 2019 May 10;235:255-267. doi: 10.1016/j.jep.2019.02.029. Epub 2019 Feb 14.
Studies have shown that the etiology and pathogenesis of colorectal cancer are closely related to the tumor microenvironment, and the cancer tissue is still in the state of "energy deficit" and has to promote energy generation through high glycolysis. Rhus chinensis Mill is a Chinese herbal medicine used to treat various types of solid tumors in China. Colorectal cancer (CRC) is a heterogeneous disease group caused by abnormal changes in glucose metabolism resulted in lactic acid production, which remodels acidosis.
Although previous studies have shown that the active compounds of Rhus chinensis Mill. can inhibit the proliferation of tumor cells, whether its triterpenoids could effectively regulate glycolysis involved in CRC have not been systematically investigated.
In this study, the extraction of triterpenoids extract from Rhus chinensis Mill. was obtained, and cell viability assay, the percentage of apoptosis for CRC cells were counted, and matrigel invasion assay and production of lactic acid and glucose uptake assay was determined. we further examined the expression of the key glycolytic enzymes and acid-sending ion channel (ASIC) family members of SW620 cells, and some key proteins in the glycolytic pathway were further verified.
Notably, triterpenoids (TER) of Rhus chinensis Mill. showed effective anti-proliferative activity and significantly altered protein levels associated with CRC cell survival and glycolysis metabolism. TER could down-regulate the expression of ASIC2, in CRC SW620 cell line. Most importantly, the levels of ASIC2 and calcineurin/nuclear factor of activated T cells (NFAT) were also down-regulated by TER. Furthermore, inhibition of activated the ASIC2-mediated calcineurin/NFAT1 pathway and target gene transcript expression of MMP-2 and MMP-9 in parallel to reduce, and resulted in the reduced invasion ability by TER treatment.
The potential pathways and targets that involved in glycolysis to excert the anti-CRC effects of main compounds in triterpenoids of Rhus chinensis Mill. were predicted by network pharmacology methods. Our findings thus provided rational evidence that inhibition of the ASIC2-induced calcineurin/NFAT pathway by triterpenoids in Rhus chinensis Mill. profoundly suppressed cell growth and invasion in CRC, which target alternative glycolysis in colorectal tumor cells, may be a useful adjuvant therapy in the treatment of colorectal cancer.
研究表明，结直肠癌的病因和发病机制与肿瘤微环境密切相关，癌组织仍处于“能量不足”状态，必须通过高糖酵解来促进能量产生。漆树是一种中药，在中国用于治疗各种类型的实体瘤。结直肠癌（CRC）是一组由葡萄糖代谢异常导致乳酸生成而重塑酸中毒的异质性疾病。
虽然先前的研究表明漆树的活性化合物可以抑制肿瘤细胞的增殖，但尚未系统研究其三萜类化合物是否能有效调节结直肠癌中涉及的糖酵解。
本研究从漆树中提取三萜类提取物，通过细胞活力测定、CRC 细胞的凋亡百分比计数、基质胶侵袭试验和乳酸及葡萄糖摄取试验来确定。我们进一步检测了 SW620 细胞中关键糖酵解酶和酸输送离子通道（ASIC）家族成员的表达，并进一步验证了糖酵解途径中的一些关键蛋白。
值得注意的是，漆树的三萜类（TER）表现出有效的抗增殖活性，并显著改变了与 CRC 细胞存活和糖酵解代谢相关的蛋白质水平。TER 可下调 CRC SW620 细胞系中 ASIC2 的表达。最重要的是，TER 还可下调 ASIC2 激活的钙调神经磷酸酶/活化 T 细胞核因子（NFAT）通路及其靶基因 MMP-2 和 MMP-9 的转录表达，从而降低 TER 处理后的侵袭能力。
通过网络药理学方法预测了漆树三萜类化合物发挥抗 CRC 作用所涉及的潜在通路和靶点。因此，我们的研究结果为 ASIC2 诱导的钙调神经磷酸酶/NFAT 通路的抑制通过漆树三萜类化合物在 CRC 中显著抑制细胞生长和侵袭提供了合理的证据，这表明靶向结直肠肿瘤细胞的替代糖酵解可能是结直肠癌治疗的一种有用的辅助治疗方法。
