DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP
Qing Zhou1, Trang Thi Thu Nguyen1,2, Jeong-Yeon Mun1
1Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA.
Abstract:
We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. Though such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell context-dependent manner (in about two-thirds of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin-interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.
Insights
Cell-penetrating peptides, like Dpep, induce tumor suppressor TXNIP, inhibiting cancer cell glucose uptake and glycolysis. This promotes cancer cell death and enhances efficacy with metformin and atovaquone.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cell-penetrating peptides (CPPs) targeting transcription factors show promise for cancer therapy.
- The precise mechanisms by which CPPs induce cancer cell death remain incompletely understood.
- Understanding CPP mechanisms is crucial for their clinical translation.
Purpose of the Study:
- To elucidate the mechanism of action for the CPP Dpep.
- To investigate the role of TXNIP in Dpep-mediated cancer cell apoptosis.
- To evaluate combination therapies of Dpep with existing cancer drugs.
Main Methods:
- Investigated Dpep's effect on glucose uptake and glycolysis in various cancer cell lines.
- Assessed the induction of thioredoxin-interacting protein (TXNIP) by Dpep.
- Utilized knockdown studies to determine TXNIP's contribution to apoptosis.
- Explored combination treatments with metformin and atovaquone.
Main Results:
- Dpep selectively inhibited glucose uptake and glycolysis in approximately two-thirds of tested cancer cell lines.
- Dpep-induced cancer cell death was dependent on the induction of TXNIP.
- TXNIP significantly contributed to Dpep-induced apoptosis in sensitive cancer cells.
- Combinations of Dpep with metformin and atovaquone demonstrated additive to synergistic anti-cancer effects.
Conclusions:
- Dpep induces TXNIP in a context-dependent manner, suppressing cancer cell glycolysis.
- TXNIP induction by Dpep is a key mediator of apoptotic cancer cell death.
- Dpep shows potential for combination therapy with drugs targeting oxidative phosphorylation for cancer treatment.
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