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Agrimoniin synergistically works with erlotinib to inhibit the proliferation of pancreatic cancer by remodeling the tumor microenvironment and suppressing lactic acid expression

ABSTRACT: Erlotinib, as an EGFR small molecule inhibitor for pancreatic cancer, its efficacy as monotherapy is limited. Combination of erlotinib and gemcitabine has shown improvement in multiple survival indicators. However, drug resistance remains a challenge. Agrimoniin, the main active ingredient in Agrimonia pilosa, has anticancer potential. Whether it can serve as a synergistic or resistance-reversing drug for erlotinib require further research. In this study, we performed subcutaneous xenograft tumor experiments, CCK8, EdU assays, flow cytometry, HE staining, immunohistochemical and western blot to explore the synergistic effects of agrimoniin and erlotinib in inhibiting pancreatic cancer. Single-cell RNA sequencing was used to explore the relationship between their synergistic effects and tumor microenvironment. Through western blot and colorimetric assays for lactic acid, we studied the connection between their synergistic effects and aerobic glycolysis as well as lactic acid expression. By employing signal pathway inhibitors and agonists, we studied the positive feedback regulatory mechanism between relevant signal pathways and lactic acid expression. We found that agrimoniin and erlotinib synergistically inhibits the proliferation and promotes the apoptosis of pancreatic cancer cells. Together, they effectively suppress signal interaction among tumor cells, stromal cells and macrophages within subcutaneous tumors. They synergistically inhibit aerobic glycolysis and lactic acid expression in pancreatic cancer. Notably, we uncover the vicious cycle between the PI3K/AKT//HIF-1α/HK2, MEK/ERK/HIF-1α/HK2 signaling pathways and lactic acid expression. Combination of agrimoniin and erlotinib remodels tumor microenvironment, reprograms aerobic glycolysis, disrupts the positive feedback loop between lactic acid and two signaling pathways, thus synergistically inhibits the proliferation of pancreatic cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278383 | GEO | 2025/03/01

REPOSITORIES: GEO

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Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H). This model is described in the article: Computational Modelling of the Metabolic States Regulated by the Kinase Akt. Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L. Frontiers in Systems Biology. 2012 Oct 13 Abstract: Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism. This model is hosted on BioModels Database and identified by: MODEL1210150000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Agrimoniin synergistically works with erlotinib to inhibit the proliferation of pancreatic cancer by remodeling the tumor microenvironment and suppressing lactic acid expression

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