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Gramicidin A blocks tumor growth and angiogenesis through inhibition of hypoxia-inducible factor in renal cell carcinoma.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2014 Apr; Vol. 13 (4), pp. 788-99. Date of Electronic Publication: 2014 Feb 03. - Publication Year :
- 2014
-
Abstract
- Ionophores are hydrophobic organic molecules that disrupt cellular transmembrane potential by permeabilizing membranes to specific ions. Gramicidin A is a channel-forming ionophore that forms a hydrophilic membrane pore that permits the rapid passage of monovalent cations. Previously, we found that gramicidin A induces cellular energy stress and cell death in renal cell carcinoma (RCC) cell lines. RCC is a therapy-resistant cancer that is characterized by constitutive activation of the transcription factor hypoxia-inducible factor (HIF). Here, we demonstrate that gramicidin A inhibits HIF in RCC cells. We found that gramicidin A destabilized HIF-1α and HIF-2α proteins in both normoxic and hypoxic conditions, which in turn diminished HIF transcriptional activity and the expression of various hypoxia-response genes. Mechanistic examination revealed that gramicidin A accelerates O(2)-dependent downregulation of HIF by upregulating the expression of the von Hippel-Lindau (VHL) tumor suppressor protein, which targets hydroxylated HIF for proteasomal degradation. Furthermore, gramicidin A reduced the growth of human RCC xenograft tumors without causing significant toxicity in mice. Gramicidin A-treated tumors also displayed physiologic and molecular features consistent with the inhibition of HIF-dependent angiogenesis. Taken together, these results demonstrate a new role for gramicidin A as a potent inhibitor of HIF that reduces tumor growth and angiogenesis in VHL-expressing RCC.
- Subjects :
- Animals
Carcinoma, Renal Cell pathology
Cell Line, Tumor
Gene Expression Regulation, Neoplastic drug effects
HEK293 Cells
Humans
Kidney Neoplasms pathology
Mice
Neoplasms, Experimental
Proteasome Endopeptidase Complex drug effects
Von Hippel-Lindau Tumor Suppressor Protein metabolism
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Basic Helix-Loop-Helix Transcription Factors antagonists & inhibitors
Carcinoma, Renal Cell drug therapy
Gramicidin pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Kidney Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 13
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 24493697
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-13-0891