Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing

Abstract

In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show that proliferating ECs increasingly depend on mitochondrial oxidative phosphorylation (OxPhos) for their increased energy demand. Under growth conditions, ECs consume three times more oxygen than quiescent ECs and work close to their respiratory limit. The increased utilization of the proton motif force leads to a reduced mitochondrial membrane potential in proliferating ECs and sensitizes to mitochondrial uncoupling. The benzoquinone embelin is a weak mitochondrial uncoupler that prevents neoangiogenesis during tumor growth and wound healing by exhausting the low respiratory reserve of proliferating ECs without adversely affecting quiescent ECs. We demonstrate that this can be exploited therapeutically by attenuating tumor growth in syngenic and xenograft mouse models. This novel metabolic targeting approach might be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment.

BID ‐dependent release of mitochondrial SMAC dampens XIAP ‐mediated immunity against Shigella

“…For analysis of mitochondrial membrane potential, HeLa cells were stained with 10 μM JC‐1 (Invitrogen) for 30 min at 37°C and analyzed by flow cytometry. For the analysis by confocal microscopy, HeLa cells were seeded on cover slips and stained with 25 nM MitoTracker ® Red CMXRos (Invitrogen) in culture media at 37°C for 30 min (Coutelle et al , ).…”

IAP antagonization promotes inflammatory destruction of vascular endothelium

“…Expanding on these findings, we first showed that the IAP antagonist Comp A inhibited tumor growth in immune‐competent mice bearing B16 melanoma tumors. In these studies, matrigel containing Comp A or vehicle was mixed with B16 cells and subcutaneously injected into the flank region of C57/Bl6 mice . In this syngeneic mouse melanoma model, tumor growth was significantly attenuated in the presence of Comp A compared to vehicle‐treated controls (Figs A and EV1A).…”

Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy

“…Therefore, repetition of cold stimulation over > 1 d was also necessary to elicit CREB1 activation and In a wound healing experiment, it was found that mitochondrial dysfunction induced by embelin hindered tissue repair [29]. CREB enhanced tissue repair by inducing the secretion of WNT1-inducible signaling protein 1 (WISP-1) [30].…”