The oncolytic peptide LTX-315 kills cancer cells through Bax/Bak-regulated mitochondrial membrane permeabilization

Oncotarget. 2015 Sep 29;6(29):26599-614. doi: 10.18632/oncotarget.5613.


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.

Keywords: LTX-315; cancer; mitochondrial membrane permeabilization; mitophagy; necrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Apoptosis
  • Cell Line, Tumor
  • Cytosol / metabolism
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Intracellular Membranes / drug effects
  • Mass Spectrometry
  • Membrane Potential, Mitochondrial*
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Mitochondria / metabolism
  • Mitophagy
  • Neoplasms / metabolism*
  • Oligopeptides / chemistry*
  • Peptides / chemistry*
  • Permeability
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism*
  • bcl-2-Associated X Protein / metabolism*


  • Antineoplastic Agents
  • BAK1 protein, human
  • BAX protein, human
  • BCL2 protein, human
  • Bak1 protein, mouse
  • Bax protein, mouse
  • LTX-315
  • Oligopeptides
  • Peptides
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Ubiquitin-Protein Ligases
  • parkin protein