Gramicidin A Blocks Tumor Growth and Angiogenesis Through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en inhibant la signalisation HIF, la gramicidine A exerce une activité anti-tumorale et anti-angiogénique dans un carcinome à cellules rénales exprimant la protéine VHL
Ionophores are hydrophobic organic molecules that disrupt cellular transmembrane potential by permeabilizing membranes to specific ions. Gramicidin A (GA) is a channel-forming ionophore that forms a hydrophilic membrane pore which permits the rapid passage of monovalent cations. Previously, we found that GA 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 GA inhibits HIF in RCC cells. We found that GA destabilized HIF-1alpha and HIF-2alpha 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 GA accelerates O2-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, GA reduced the growth of human RCC xenograft tumors without causing significant toxicity in mice. GA-treated tumors also displayed physiological and molecular features consistent with the inhibition of HIF-dependent angiogenesis. Taken together, these results demonstrate a new role for GA as a potent inhibitor of HIF that reduces tumor growth and angiogenesis in VHL-expressing RCC.
http://mct.aacrjournals.org/content/early/2014/02/01/1535-7163.MCT-13-0891.abstract