Abstract
Within the last decade, several peptides have been identified according to their ability to inhibit the growth of microbial pathogens. These antimicrobial peptides (AMPs) are a part of the innate immune system of all living organisms. Many studies on their effects on prokaryotic microorganisms have been reported; some of these peptides have cytotoxic properties although the molecular mechanisms underlying their activity on eukaryotic cells remain poorly understood. Smp24 and Smp43 are novel cationic AMPs which were identified from the venom of the Egyptian scorpion Scorpio maurus palmatus. Smp24 and Smp43 showed potent activity against both Gram-positive and Gram-negative bacteria as well as fungi. Here we describe cytotoxicity of these peptides towards two acute leukaemia cell lines (myeloid (KG1-a) and lymphoid (CCRF-CEM) leukaemia cell lines) and three non-tumour cell lines CD34+ (hematopoietic stem progenitor from cord blood), HRECs (human renal epithelial cells) and HaCaT (human skin keratinocytes). Smp24 and Smp43 (4–256 µg/ml) decreased the viability of all cell lines, although HaCaT cells were markedly less sensitive. With the exception HaCaT cells, the caspase-1 gene was uniquely up-regulated in all cell lines studied. However, all cell lines showed an increase in downstream interleukin-1β (IL-1β) expression. Transmission electron microscope studies revealed the formation of cell membrane blebs and the appearance of autolysosomes and lipid droplets in all cell lines; KG1-a leukemia cells also showed the unique appearance of glycogen deposits. Our results reveal a novel mechanism of action for scorpion venom AMPs, activating a cascade of events leading to cell death through a programmed pyroptotic mechanism.
Highlights
Antimicrobial peptides (AMPs) are found throughout the animal kingdom and represent an ancient host defence mechanism of the innate immune system (Zasloff, 2002; Lai and Gallo, 2009; Bahar and Ren, 2013)
Previous results have demonstrated that Smp24 and Smp43 disrupted the integrity of cell membranes as evidenced by the release of cytoplasmic lactate dehydrogenase in a range of tumour and non-tumour cell lines as well as primary cells18. To examine this cytotoxic event in more detail, all cell lines were double stained with Hoechst 33342 dye and propidium iodide (PI) after treatment with either Smp24 or Smp43
These results suggest that the cytotoxic effects of Smp24 and Smp43 are due to a lytic mechanism
Summary
Antimicrobial peptides (AMPs) are found throughout the animal kingdom and represent an ancient host defence mechanism of the innate immune system (Zasloff, 2002; Lai and Gallo, 2009; Bahar and Ren, 2013). They are increasingly recognized as a potential source of new broad-spectrum antibiotics, to combat the steady and alarming rise in the resistance of pathogenic microorganisms to conventional drugs (Guilhelmelli et al, 2013; Nuti et al, 2017). The appearance of phosphatidylserine on the outer membrane leaflet regulates malignant transformation by primarily suppressing anti-tumour immune responses (Utsugi et al, 1991; Fadok et al, 2000)
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