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Novel Bradykinin Receptor Inhibitors Inhibit Proliferation and Promote the Apoptosis of Hepatocellular Carcinoma Cells by Inhibiting the ERK Pathway.

ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Studies have shown that bradykinin (BK) is highly expressed in liver cancer. We designed the novel BK receptor inhibitors J051-71 and J051-105, which reduced the viability of liver cancer cells and inhibited the formation of cancer cell colonies. J051-71 and J051-105 reduced cell proliferation and induced apoptosis in HepG2 and BEL-7402 cells, which may be due to the inhibition of the extracellular regulated protein kinase (ERK) signaling pathway. In addition, these BK receptor inhibitors reversed the cell proliferation induced by BK in HepG2 and BEL-7402 cells by downregulating B1 receptor expression. Inhibiting B1 receptor expression decreased the protein levels of p-ERK and reduced the malignant progression of HCC, providing a potential target for HCC therapy.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8272207 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Novel Bradykinin Receptor Inhibitors Inhibit Proliferation and Promote the Apoptosis of Hepatocellular Carcinoma Cells by Inhibiting the ERK Pathway.

Wang Yiou Y Zhang Bingxue B Huang Yibing Y Yao Wenjun W Tao Fei F Chen Yuxin Y

Molecules (Basel, Switzerland) 20210626 13

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Studies have shown that bradykinin (BK) is highly expressed in liver cancer. We designed the novel BK receptor inhibitors J051-71 and J051-105, which reduced the viability of liver cancer cells and inhibited the formation of cancer cell colonies. J051-71 and J051-105 reduced cell proliferation and induced apoptosis in HepG2 and BEL-7402 cells, which may be due to the inhibition of the extracellular regulated protein kinase ...[more]

PMID: 34206871

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Project description:Glucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is complex and still debatable. One likely cellular target of GCs are monocytes/macrophages. The role of GCs in monocyte survival is also debated. Although both granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) are important regulators of macrophage lineage functions including their survival, the former is often associated with proinflammatory functions while the latter is important in lineage homeostasis. We report here that the GC, dexamethasone, induces apoptosis in GM-CSF-treated human monocytes while having no impact on M-CSF-induced monocyte survival. To understand how GCs, GM-CSF, and M-CSF are regulating monocyte survival and other functions during inflammation, we firstly examined the transcriptomic changes elicited by these three agents in human monocytes, either acting alone or in combination. Transcriptomic and Ingenuity pathway analyses found that dexamethasone differentially modulated dendritic cell maturation and TREM1 signaling pathways in GM-CSF-treated and M-CSF-treated monocytes, two pathways known to be regulated by ERK1/2 activity. These analyses led us to provide evidence that the GC inhibits ERK1/2 activity selectively in GM-CSF-treated monocytes to induce apoptosis. It is proposed that this inhibition of ERK1/2 activity leads to inactivation of p90 ribosomal-S6 kinase and Bad dephosphorylation leading in turn to enhanced caspase-3 activity and subsequent apoptosis. Furthermore, pharmacological inhibition of GC receptor activity restored the ERK1/2 signaling and prevented the GC-induced apoptosis in GM-CSF-treated monocytes. Increased tissue macrophage numbers, possibly from enhanced survival due to mediators such as GM-CSF, can correlate with inflammatory disease severity; also reduction in these numbers can correlate with the therapeutic benefit of a number of agents, including GCs. We propose that the ERK1/2 signaling pathway promotes survival of GM-CSF-treated proinflammatory monocytes, which can be selectively targeted by GCs as a novel mechanism to reduce local monocyte/macrophage numbers and hence inflammation.

Project description:Hepatocellular carcinoma(HCC) has a high mortality and morbidity rate and seriously jeopardizes human life. Chemicals and chemotherapeutic agents have been experiencing problems such as side effects and drug resistance in the treatment of HCC, which cannot meet the needs of clinical treatment. Therefore, finding novel low-toxicity and high-efficiency anti-hepatocellular carcinoma drugs and exploring their mechanisms of action have become the current problems to be solved in the treatment of HCC. Several studies have reported anticancer effects of inotodiol. This study focuses on the anticancer effect of inotodiol in HCC cells and its molecular mechanism, aiming to explore its anticancer effect in depth. The CCK8 assay was utilized to assess cell viability, the scratch assay was utilized to detect migration ability, the clone formation assay was utilized to detect clonogenic ability, and flow cytometry was utilized to analyze apoptosis and cell cycle. Animal experiments was utilized to verify the inhibitory effect of inotodiol on HCC. Meanwhile, western blotting was utilized to detect proteins associated with apoptosis, cell cycle and MAPK/ERK pathway. These results showed that inotodiol has the ability to promote apoptosis, as well as inhibit the ability of cell proliferation, migration, and clonogenic ability. The cell cycle was arrested in G1 phase, when the expression of CDK2, CDK4, CDK6 and Cyclin D were inhibited. In addition, inotodiol showed to induce apoptosis, characterized by an increase in Bax expression, a decrease in Bcl-2, Bcl-XL and MCL1 expression, the initiation of cleaved PARP1 and cleaved caspase 3, and inhibition of the MAPK/ERK pathway. Animal studies demonstrated that inotodiol possessed the ability to suppress tumor growth in nude mice models, at the same time, there was no significant impact on the body weight and organs of the mice. In conclusion, the findings presented herein compellingly suggest that inotodiol may serve as a promising candidate for the treatment of hepatocellular carcinoma (HCC).

Dataset Information

Novel Bradykinin Receptor Inhibitors Inhibit Proliferation and Promote the Apoptosis of Hepatocellular Carcinoma Cells by Inhibiting the ERK Pathway.

Publications

Novel Bradykinin Receptor Inhibitors Inhibit Proliferation and Promote the Apoptosis of Hepatocellular Carcinoma Cells by Inhibiting the ERK Pathway.

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