期刊
PHYTOMEDICINE
卷 103, 期 -, 页码 -出版社
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2022.154229
关键词
Traditional Chinese medicine; PKM2; Gastric cancer; Exosomes; Tumor-associated macrophages; Tumor microenvironment
资金
- National Natural Science Foundation of China [82174197, 81973609, 81973782, 81704031]
- Science and Technology Planning Project of Jiangsu Province, China [BK20211392]
- Jiangsu Provincial Medical Youth Talent [QNRC2016641]
- 333 Project of Jiangsu Province [LGY2018065]
- Jiangsu Provincial Hospital of Traditional Chinese Medicine Academic Talent Program [Y2018RC33]
- Postgraduate Research &Practice Innovation Program of Jiangsu Province [SJCX21_0692, SJCX21-0740]
- Foundation of Administration of Traditional Chinese Medicine of Jiangsu Province, China [YB2017016]
mJPYZ can reduce the delivery of exosomal PKM2 from tumor cells to macrophages, alleviate exosomal PKM2-induced differentiation of M2 macrophages, and ultimately inhibit gastric cancer progression.
Background: Modified Jianpi Yangzheng decoction (mJPYZ), as an empirical decoction of Traditional Chinese medicine has been shown significantly to prolong the survival of patients with advanced stage gastric cancer. Pyruvate kinase M2 (PKM2), has attracted attention for its important role on cellular aerobic glycolysis, however, few studies focus on PKM2 non-metabolic roles in tumor progression. Purpose: Our study aimed to investigate the potential role of gastric cancer exosomes containing PKM2 in regulating tumor-associated macrophages (TAM) and the mechanism of mJPYZ against gastric cancer.Methods: Colony Formation Assay, flow cytometry and TUNEL staining were employed to estimate the effect of mJPYZ on gastric cancer in tumor-bearing mice and cells. Western blot analyzed apoptosis-related protein expression changes. Network pharmacology and bioinformatics predicted potential exosomes modulation of mJPYZ in gastric cancer. Exosomes were isolated and co-cultured with TAM. Diff-Quik Staining observed the TAM morphological changes when incubating with gastric cancer cells exosomes. Flow cytometry and immunofluorescence were performed to demonstrate whether exosomes PKM2 involved in TAM polarization.Results: mJPYZ induced apoptosis of gastric cancer cells by targeting PKM2 and downregulating PI3K/Akt/mTOR axis in vivo and in vitro. Network pharmacology showed potential exosomes modulation of mJPYZ in gastric cancer. We extracted exosomes and found mJPYZ decreased the abundance of serum exosomes PKM2 in patients with advanced gastric cancer and xenograft tumor model. Additionally, we firstly detected and confirmed that PKM2 is a package protein of exosomes extracted from gastric cancer cells, and mJPYZ could diminish the content of exosomal PKM2 in gastric cancer cells. Importantly, mJPYZ reduced the delivery of exosomal PKM2 from tumor cells to macrophages, and alleviated exosomal PKM2-induced differentiation of M2-TAM in tumor microenvironment, eventually inhibited gastric cancer progression.Conclusion: Gastric cancer exosomes containing PKM2 could lead to M2 macrophages differentiation, thereby promoting gastric cancer progression. Our findings provide a rationale for potential application of mJPYZ in the treatment of gastric cancer via PKM2.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据