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The Oligostilbene Gnetin H Is a Novel Glycolysis Inhibitor That Regulates Thioredoxin Interacting Protein Expression
Shivendra Singh1, Flavia De Carlo1, Mohamed A Ibrahim1
1National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Abstract:
Since aerobic glycolysis was first observed in tumors almost a century ago by Otto Warburg, the field of cancer cell metabolism has sparked the interest of scientists around the world as it might offer new avenues of treatment 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 (Phen), 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 on regulating a key gene involved in the homeostasis of cellular glucose. GH in combination with phenformin also substantially enhances the 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 for inducing metabolic catastrophe in cancer cells and reducing their growth.
Insights
Gnetin H (GH) is a novel glycolysis inhibitor that effectively reduces cancer cell growth and lactic acid production. Combining GH with phenformin induces metabolic catastrophe, offering a potent new cancer treatment strategy.
Area of Science:
- Oncology
- Cancer Metabolism
- Biochemistry
Background:
- Aerobic glycolysis, observed by Otto Warburg, is a hallmark of cancer metabolism.
- Cancer cell metabolism presents potential therapeutic targets for novel treatments.
- Targeting cancer metabolism offers new avenues for treating malignant cells.
Purpose of the Study:
- To discover novel glycolysis inhibitors for cancer treatment.
- To investigate the effects of gnetin H (GH) on cancer cell metabolism.
- To evaluate the synergistic effects of GH and phenformin in cancer cells.
Main Methods:
- Utilized RNA-Seq on T98G glioblastoma cells treated with GH.
- Assessed metabolic activity and lactic acid synthesis.
- Measured p-AMPK levels in combination treatments.
Main Results:
- Gnetin H (GH) significantly inhibited glycolysis, decreasing metabolic activity and lactic acid synthesis.
- GH demonstrated a potent cytostatic effect on melanoma and glioblastoma cells.
- GH treatment led to an 80-fold reduction in thioredoxin interacting protein (TXNIP) expression.
- Combination of GH and phenformin enhanced p-AMPK levels, indicating metabolic catastrophe.
Conclusions:
- Gnetin H (GH) is a novel glycolysis inhibitor with significant anti-cancer effects.
- GH directly regulates TXNIP, a key gene in glucose homeostasis.
- Concurrent use of GH and phenformin induces metabolic catastrophe in cancer cells, inhibiting growth.
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