Gramicidin A blocks tumor growth and angiogenesis through inhibition of hypoxia-inducible factor in renal cell carcinoma.
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.
Authors' Affiliations: Department of Biological Sciences, University of Delaware, Newark; Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware; and Center for Thoracic Disease and Transplantation, Heart and Lung Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.
Justin M
JM
David
Tori A
TA
Owens
Landon J
LJ
Inge
Ross M
RM
Bremner
Ayyappan K
AK
Rajasekaran
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006096:Gramicidin / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D006096:Gramicidin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046988:Proteasome Endopeptidase Complex; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1