Brevinin-2R semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway

• Brevinin-2R is a novel non-hemolytic defensin that was isolated from the skin of the frog Rana ridibunda . It exhibits preferential cytotoxicity towards malignant cells, including Jurkat (T-cell leukemia), BJAB (B-cell lymphoma), HT29/219, SW742 (colon carcinomas), L929 (fibrosarcoma), MCF-7 (breast adenocarcinoma), A549 (lung carcinoma), as compared to primary cells including peripheral blood mononuclear cells (PBMC), T cells and human lung fibroblasts. Jurkat and MCF-7 cells overexpressing Bcl2, and L929 and MCF-7 over-expressing a dominant-negative mutant of a pro-apoptotic BNIP3 (ΔTM-BNIP3) were largely resistant towards Brevinin-2R treatment. The decrease in mitochondrial membrane potential (ΔΨm), or total cellular ATP levels, and increased reactive oxygen species (ROS) production, but not caspase activation or the release of apoptosis-inducing factor (AIF) or endonuclease G (Endo G), were early indicators of Brevinin-2R-triggered death. Brevinin-2R interacts with both early and late endosomes. Lysosomal membrane permeabilization inhibitors and inhibitors of cathepsin-B and cathepsin-L prevented Brevinin-2R-induced cell death. Autophagosomes have been detected upon Brevinin-2R treatment. Our results show that Brevinin-2R activates the lysosomalmitochondrial death pathway, and involves autophagy-like cell death.

Ämnesord

Medical and Health Sciences  (hsv)

Clinical Medicine  (hsv)

Cancer and Oncology  (hsv)

Medicin och hälsovetenskap  (hsv)

Klinisk medicin  (hsv)

Cancer och onkologi  (hsv)

Medical Biotechnology  (hsv)

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)  (hsv)

Medicinsk bioteknologi  (hsv)

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)  (hsv)

Natural Sciences  (hsv)

Biological Sciences  (hsv)

Cell Biology  (hsv)

Naturvetenskap  (hsv)

Biologiska vetenskaper  (hsv)

Cellbiologi  (hsv)

Biochemistry and Molecular Biology  (hsv)

Biokemi och molekylärbiologi  (hsv)

Nyckelord

antibacterial peptide; defensin; Brevinin-2R; cell death; caspase activation; lysosomotrophic agent; late and early endosome; ROS; mitochondrial pathway; targetted cancer therapy