Zhangzhou Pientzehuang Pharmaceutical Co., Ltd., Huporoad, Zhangzhou, 363000, People's Republic of China.
Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou, 363000, Fujian, People's Republic of China.
Sci Rep. 2023 Feb 2;13(1):1897. doi: 10.1038/s41598-023-29116-8.
The Chinese medicine formula Pien Tze Huang (PZH) has been applied to the treatment of various diseases, the reported anti-tumor mechanisms included regulation of inflammation-associated cytokine secretion and cancer growth pathways. However, the potential influence of PZH on tumor metabolism remains unclear. This study aimed to investigate the global effect of PZH on hepatocellular carcinoma (HCC) compared with the anti-tumor agent sorafenib based on tandem mass tag (TMT) label proteomic and phosphoproteomic analysis in addition to parallel reaction monitoring (PRM) verification. It was observed that PZH could inhibit tumor weight by 59-69% in different concentrations. TMT proteomic studies indicated that fructose/mannose metabolism and glucagon signaling pathway in PZH group, and arachidonic acid metabolism and PPAR signaling pathway in sorafenib group, were significantly enriched, while glycolysis/gluconeogenesis pathway was found to be enriched remarkably both in PZH and sorafenib groups in TMT phosphoproteomic study. PRM verification further indicated that both PZH and sorafenib could down-regulate phosphorylations of the glycolytic enzymes phosphofructokinases 1, fructose-bisphosphate Aldolase A, phosphoglycerate mutase 2 and lactate dehydrogenase A chain, while phosphorylations of long chain fatty acid CoA ligase in fatty acid activation and acetyl-coenzyme A synthetase in glycolysis were significantly inhibited by PZH and sorafenib, respectively. This study proposed that PZH shared a similar anti-tumor mechanism of metabolic regulation to sorafenib, but differed in the regulation of some metabolic nodes. This is the first time to uncover the relationship between the anti-tumor effect of PZH and metabolic related enzymes, which distinguished from the known mechanisms of PZH. These data provided the potential molecular basis for PZH acting as a therapeutic drug for HCC, and offered cues of manipulation on Warburg effect under the treatment of PZH.
中药配方品黄（PZH）已应用于治疗各种疾病，据报道其抗肿瘤机制包括调节炎症相关细胞因子分泌和癌症生长途径。然而，PZH 对肿瘤代谢的潜在影响尚不清楚。本研究旨在基于串联质量标签（TMT）标记蛋白质组学和磷酸化蛋白质组学分析，以及平行反应监测（PRM）验证，比较 PZH 与抗肿瘤剂索拉非尼对肝细胞癌（HCC）的整体影响。结果观察到，PZH 以不同浓度处理可使肿瘤重量抑制 59-69%。TMT 蛋白质组学研究表明，PZH 组中果糖/甘露糖代谢和胰高血糖素信号通路，以及索拉非尼组中花生四烯酸代谢和 PPAR 信号通路明显富集，而 TMT 磷酸化蛋白质组学研究中发现糖酵解/糖异生途径在 PZH 和索拉非尼组中均明显富集。PRM 验证进一步表明，PZH 和索拉非尼均可下调糖酵解酶磷酸果糖激酶 1、果糖二磷酸醛缩酶 A、磷酸甘油酸变位酶 2 和乳酸脱氢酶 A 链的磷酸化，而长链脂肪酸辅酶 A 连接酶在脂肪酸活化和乙酰辅酶 A 合成酶在糖酵解中的磷酸化则分别被 PZH 和索拉非尼显著抑制。本研究提出，PZH 与索拉非尼具有相似的代谢调节抗肿瘤机制，但在一些代谢节点的调节上存在差异。这是首次揭示 PZH 的抗肿瘤作用与代谢相关酶之间的关系，与 PZH 的已知机制不同。这些数据为 PZH 作为 HCC 治疗药物的作用提供了潜在的分子基础，并为 PZH 治疗下对沃伯格效应的调控提供了线索。
