The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells
Permanent lenke
https://hdl.handle.net/10037/8679Dato
2015-10-13Type
Journal articleTidsskriftartikkel
Peer reviewed
Sammendrag
Host defense peptides (HDPs) are naturally occurring molecules found in most
species, in which they play a significant role in the first line defense against intruding
pathogens, and several HDPs have been shown to possess anticancer activity.
Structure-activity relationship studies on the HDP bovine lactoferricin revealed
a de novo design of a nonamer peptide LTX-315, with oncolytic properties.
In the present study, we investigated the oncolytic activity of LTX-315 in human
melanoma cells (A375). LTX-315 induced a rapid plasma membrane disruption and
cell death within 2 hours. At a low concentration, fluorescence-labeled LTX-315
was internalized and accumulated in cytoplasmic vacuoles in close proximity to the
mitochondria. The mitochondrial membrane potential was shown to depolarize as
a consequence of LTX-315 treatment and at ultrastructural level, the mitochondria
morphology was significantly altered. Release of danger signals (DAMPs) such as
ATP, Cytochrome C and HMGB1 into the cell supernatant of cultured cells was evident
minutes after peptide treatment.
The oncolytic effect of LTX-315 involving perturbation of both the cell membrane
and the mitochondria with subsequent release of DAMPs may highlight the ability of
LTX-315 to induce complete regression and long-term protective immune responses
as previously reported in experimental animal models.