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The Oligostilbene Gnetin-H is a Novel Glycolysis Inhibitor that Regulates Thioredoxin Interacting Protein Expression and Synergizes with OXPHOS Inhibitor in Cancer Cells

ABSTRACT: Since aerobic glycolysis has been first observed in tumors almost a century ago by Otto Warburg, the field of cancer cell metabolism sparked the interest of scientists around the world as it might offer new avenues of treatments for malignant cells. Our current study claims the discovery of Gnetin-H (GH) as a novel glycolysis inhibitor that can decrease metabolic activity and lactic acid synthesis and displays a strong cytostatic effect in melanoma and glioblastoma cells. Compared to most of the other glycolysis inhibitors used in combination with the complex-1 mitochondrial inhibitor Phenformin, GH more potently inhibited cell growth. RNA-Seq with the T98G glioblastoma cell line treated with GH showed more than an 80-fold reduction in Thioredoxin Interacting Protein (TXNIP) expression indicating that GH has a direct effect in regulating a key gene involved in the homeostasis of cellular glucose. GH in combination with Phenformin also substantially enhanced levels of p-AMPK, a marker of metabolic catastrophe. These findings suggest that the concurrent use of the glycolytic inhibitor GH with a complex-1 mitochondrial inhibitor could be used as a powerful tool to induce metabolic catastrophe in cancer cells and reduce their growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224692 | GEO | 2023/05/17

REPOSITORIES: GEO

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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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The Oligostilbene Gnetin-H is a Novel Glycolysis Inhibitor that Regulates Thioredoxin Interacting Protein Expression and Synergizes with OXPHOS Inhibitor in Cancer Cells

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