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Connective Tissue Growth Factor, a Potential Prognostic Marker of Triple Negative Breast Cancer treatment

ABSTRACT: Triple negative breast cancer (TNBC) patient with high level of connective tissue growth factor (CTGF) show poor survival and prognosis. Identification of novel target contributes to the development of TNBC treatment. Kahweol, a coffee diterpene molecule, is a natural compound with pharmacological activities such as anti-inflammatory, anti-angiogenetic, and apoptotic effect in several cancer cells. In this study, we demonstrated the involvement of CTGF expression level in TNBC treatment. Experiments were performed on MDA-MB 231, a TNBC cell line. Firstly, functional annotation and gene set enrichment analysis found that the CTGF involves in migratory pathways in TNBC treatment. We also investigated that kahweol regulates CTGF expression and functions as antitumor compound resulting in inhibition of cell migration and colony formation in TNBC. Next, CTGF knockdown synergically suppressed cell motility with kahweol. Migratory ability and colony conformation were also performed in vitro to confirm the results from functional annotation assay. Overall, our results suggest that CTGF is a potential target as a prognostic marker predicting the prognosis of TNBC treatment, and kahweol is a potential antitumor compound to regulate CTGF expression for TNBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199503 | GEO | 2024/02/13

REPOSITORIES: GEO

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Project description:Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options and a poor prognosis. TNBC exists widely reprogrammed lipid metabolism, and its metabolic-associated proteins and oncometabolites are promising as potential therapeutic targets. Dandelion (Taraxacum mongolicum) is a classical herbal medicine used to treat breast diseases based on traditional Chinese medicine theory and was reported to have antitumor effects and lipid regulatory capacities. Our previous study showed that dandelion extract was effective against TNBC. However, whether dandelion extract could regulate the lipid metabolisms of TNBC and exert its antitumor effects via interfering with lipids metabolism remained unclear. In this study, an integrated approach combined with network pharmacology and multi-omics techniques (including proteomics, metabolomics, and lipidomics) was performed to investigate the potential regulatory mechanisms of dandelion extract against TNBC. We first determined the antitumor effects of dandelion extract in vitro and in vivo. Then, network pharmacology analysis speculated the antitumor effects involving various metabolic processes, and the multi-omics results of the cells, tumor tissues, and plasma revealed the changes in the metabolites and metabolic-associated proteins after dandelion extract treatment. The alteration of glycerophospholipids and unsaturated fatty acids were the most remarkable types of metabolites. Therefore, the metabolism of glycerophospholipids and unsaturated fatty acids, and their corresponding proteins CHKA and FADS2, were considered the primary regulatory pathways and biomarkers of dandelion extract against TNBC. Subsequently, experimental validation showed that dandelion extract decreased CHKA expression, leading to the inhibition of the PI3K/AKT pathway and its downstream targets, SREBP and FADS2. Finally, the molecular docking simulation suggested that picrasinoside F and luteolin in dandelion extract had the most highly binding scores with CHKA, indicating they may be the potential CHKA inhibitors to regulate glycerophospholipids metabolisms of TNBC. In conclusion, we confirmed the antitumor effects of dandelion extract against TNBC cells in vitro and demonstrated that dandelion extract could interfere with glycerophospholipids and unsaturated fatty acids metabolism via downregulating the CHKA expression and thus inhibiting PI3K/AKT/SREBP/FADS2 axis.

Project description:Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to the absence of well-defined molecular targets and high invasive and proliferative capacities of these cells. Current treatments against TNBC have shown minimal activity due to the high recurrence rate in the patients. Therefore, a pressing need for novel and efficacious therapies against TNBC. Here, we found a novel small molecule inhibitor (NSC33353) with potent anti-tumor activity against TNBC cells. Anti-proliferative effects of NSC small molecule inhibitor were determined using 2D and 3D culture cell proliferation assays. Using proteomics, NGS and enrichment analysis, we globally investigated top regulatory pathways affected by this compound in TNBC cells. Subsequently, we validated the proteomics and NGS analysis data using seahorse and enzymatic assays. Finally, we showed the inhibitor anti-tumor effects and confirmed its potential mechanism in vivo. In this report, we showed that a novel NSC33353 small molecule inhibitor reduced the proliferation of TNBC cells. Proteomic analysis confirmed a significant metabolic reprograming including suppression of glycolysis and oxidative phosphorylation after treatment. Furthermore, we found that treatment with NSC33353 small molecule inhibitor impaired glycolysis and oxidative phosphorylation via modulating the activity of metabolic regulator enzymes. Altogether, our data indicate that NSC33353 small molecule inhibitor may exhibit anti-tumor activity in TNBC cells and provide a rationale for further investigation of the potential of NSC small molecule inhibitor as an attractive therapeutic drug for TNBC. Doxorubicin is one of the most effective agents in the treatment of TNBC and resistance to this drug is a major problem. We show that the combination of NSC33353 and doxorubicin synergistically suppressed the growth of TNBC cells suggesting the combination enhances the sensitivity to doxorubicin. Further in-depth investigations are required to evaluate the exact targets and mechanism of this potent small molecule inhibitor, and its anti-neoplasm effects on TNBC in vivo.

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Connective Tissue Growth Factor, a Potential Prognostic Marker of Triple Negative Breast Cancer treatment

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