CXCL12 secreted by pancreatic stellate cells accelerates gemcitabine resistance of pancreatic cancer by enhancing glycolytic reprogramming.

IF 2.5 2区 生物学 Q3 CELL BIOLOGY
Animal Cells and Systems Pub Date : 2022-07-04 eCollection Date: 2022-01-01 DOI:10.1080/19768354.2022.2091019
Xiangyu Lu, Yilei Wu, Rui Cao, Xiaojiong Yu, Jun Gong
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引用次数: 4

Abstract

Pancreatic stellate cells (PSCs) are the primary cell components of pancreatic cancer (PC) and are involved in tumor growth, metastasis and resistance. However, the role and the mechanism of PSCs in gemcitabine (GEM) resistance to PC still need more investigation. We found that CXCL12 mRNA and secreted CXCL12 protein were higher in PSCs after GEM treatment. The conditioned medium (CM) from GEM-treated PSCs reduced the GEM sensitivity of PC cells. Blocking of CXCL12 in CM by anti-CXCL12 antibody partly restored the GEM sensitivity of PC cells. Blocking of CXCL12 decreased glucose consumption, lactate production, ECAR, and glycolysis-related gene expression in PC cells. The PI3K/AKT/mTOR pathway was activated by the binding of CXCL12 and CXCR4. Moreover, CXCR4 mRNA and protein expressions in PC cells were increased after GEM treatment. Our results indicated the cross-talk between PSCs and PC cells during GEM chemotherapy. CXCL12 secreted by PSCs reduces GEM sensitivity of PC cells by binding to CXCR4 and activating PI3K/AKT/mTOR-glycolysis pathway in PC. Our findings would lay the foundation for solving GEM resistance in PC.

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胰腺星状细胞分泌的CXCL12通过增强糖酵解重编程加速胰腺癌对吉西他滨的耐药。
胰腺星状细胞(Pancreatic stellate cells, PSCs)是胰腺癌(Pancreatic cancer, PC)的主要细胞成分,参与肿瘤的生长、转移和抵抗。然而,PSCs在吉西他滨(GEM)耐PC中的作用和机制仍有待进一步研究。我们发现,GEM处理后的PSCs中CXCL12 mRNA和分泌的CXCL12蛋白均升高。来自GEM处理的psc的条件培养基(CM)降低了PC细胞对GEM的敏感性。用抗CXCL12抗体阻断CM中的CXCL12,可部分恢复PC细胞对GEM的敏感性。阻断CXCL12可降低PC细胞的葡萄糖消耗、乳酸生成、ECAR和糖酵解相关基因表达。PI3K/AKT/mTOR通路被CXCL12和CXCR4的结合激活。此外,GEM处理后PC细胞中CXCR4 mRNA和蛋白的表达增加。我们的研究结果表明,在GEM化疗期间,PSCs和PC细胞之间存在串扰。PSCs分泌的CXCL12通过与CXCR4结合,激活PC中PI3K/AKT/ mtor -糖酵解通路,降低PC细胞对GEM的敏感性。我们的发现将为解决GEM在PC中的耐药性奠定基础。
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来源期刊
Animal Cells and Systems
Animal Cells and Systems 生物-动物学
CiteScore
4.50
自引率
24.10%
发文量
33
审稿时长
6 months
期刊介绍: Animal Cells and Systems is the official journal of the Korean Society for Integrative Biology. This international, peer-reviewed journal publishes original papers that cover diverse aspects of biological sciences including Bioinformatics and Systems Biology, Developmental Biology, Evolution and Systematic Biology, Population Biology, & Animal Behaviour, Molecular and Cellular Biology, Neurobiology and Immunology, and Translational Medicine.
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