Abstract
LTX-315 has been developed as an amphipathic cationic peptide that kills cancer cells. Here, we investigated the putative involvement of mitochondria in the cytotoxic action of LTX-315. Subcellular fractionation of LTX-315-treated cells, followed by mass spectrometric quantification, revealed that the agent was enriched in mitochondria. LTX-315 caused an immediate arrest of mitochondrial respiration without any major uncoupling effect. Accordingly, LTX-315 disrupted the mitochondrial network, dissipated the mitochondrial inner transmembrane potential, and caused the release of mitochondrial intermembrane proteins into the cytosol. LTX-315 was relatively inefficient in stimulating mitophagy. Cells lacking the two pro-apoptotic multidomain proteins from the BCL-2 family, BAX and BAK, were less susceptible to LTX-315-mediated killing. Moreover, cells engineered to lose their mitochondria (by transfection with Parkin combined with treatment with a protonophore causing mitophagy) were relatively resistant against LTX-315, underscoring the importance of this organelle for LTX-315-mediated cytotoxicity. Altogether, these results support the notion that LTX-315 kills cancer cells by virtue of its capacity to permeabilize mitochondrial membranes.
Highlights
Cancer cells heavily rely on mitochondrial metabolism due to their particular growth characteristics [1,2,3,4], implying that targeting mitochondria may constitute a relevant strategy for reducing proliferation or killing tumor cells [5,6,7]
The present data indicate that LTX-315 stimulates cell death via its capacity to induce mitochondrial membrane permeabilization
This idea is supported by several levels of correlative evidence, namely (i) the enrichment of the peptide in the mitochondrial fraction of LTX-315-treated cells; (ii) the capacity of LTX-315 to inhibit oxidative phosphorylation; (iii) the ability of LTX-315 to cause mitochondrial fragmentation; (iv) the dissipation of the ∆ψm induced by LTX-315; (v) the permeabilization of the outer mitochondrial membrane causing the release of SMAC and cytochrome c
Summary
Cancer cells heavily rely on mitochondrial metabolism due to their particular growth characteristics [1,2,3,4], implying that targeting mitochondria may constitute a relevant strategy for reducing proliferation or killing tumor cells [5,6,7]. Multiple anticancer agents have been developed with the scope of targeting www.impactjournals.com/oncotarget mitochondria. Among such mitochondriotropic agents, those endowed with the capacity of permeabilizing mitochondrial membranes are interesting [5, 6, 8]. Those endowed with the capacity of permeabilizing mitochondrial membranes are interesting [5, 6, 8] Such agents can stimulate the intrinsic apoptotic pathway (which involves an obligate step of mitochondrial outer membrane permeabilization, MOMP) in a direct fashion [9]. Direct MOMP inducers can ignite cell death pathways downstream of the usual roadblocks (such as inactivation of the p53 pathway) that mediate resistance to many anticancer agents
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