Abstract
Defensins form an integral part of the cationic host defence peptide (HDP) family, a key component of innate immunity. Apart from their antimicrobial and immunomodulatory activities, many HDPs exert multifaceted effects on tumour cells, notably direct oncolysis and/or inhibition of tumour cell migration. Therefore, HDPs have been explored as promising anticancer therapeutics. Human β-defensin 2 (HBD-2) represents a prominent member of human HDPs, being well-characterised for its potent pathogen-killing, wound-healing, cytokine-inducing and leukocyte-chemoattracting functions. However, its anticancer effects remain largely unknown. Recently, we demonstrated that HBD-2 binds strongly to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), a key mediator of defensin-induced cell death and an instructional messenger during cell migration. Hence, in this study, we sought to investigate the lytic and anti-migratory effects of HBD-2 on tumour cells. Using various cell biological assays and confocal microscopy, we showed that HBD-2 killed tumour cells via acute lytic cell death rather than apoptosis. In addition, our data suggested that, despite the reported PI(4,5)P2 interaction, HBD-2 does not affect cytoskeletal-dependent tumour cell migration. Together, our findings provide further insights into defensin biology and informs future defensin-based drug development.
Highlights
Defensins, a group of cysteine-containing, β-sheet-rich, cationic host defence peptide (HDP), are important contributors to innate immunity, providing crucial infection-combating mechanisms [1,2].Despite the varying primary sequence, the tertiary structure of defensins remains relatively similar across different kingdoms, suggesting an evolutionarily conserved mechanism of action [3]
We found that in a dose-dependent manner, HBD-2 killed various tumour cell lines, including cervical cancer cells (HeLa), prostate cancer cells (PC3), breast cancer cells (MCF-7 and basal cell carcinoma (BCC)) with IC50 of ≥50 μM, with minimal cytotoxic effects against monocytic lymphoma cells (U937) and metastatic breast carcinoma cells (MDA-MB-231)
As Propidium Iodide (PI)(4,5)P2 -binding defensins can induce lytic cell death, characterised by large membrane blebbing and membrane permeabilisation, we investigated the ability of HBD-2 to lyse tumour cells
Summary
Despite the varying primary sequence, the tertiary structure of defensins remains relatively similar across different kingdoms, suggesting an evolutionarily conserved mechanism of action [3]. Discovered for their potent antimicrobial activity, defensins have recently gained increased interest due to their functional complexity, among which are tumour-suppressing effects [4,5,6]. Several plant and human defensins such as Nicotiana alata defensin 1, NaD1, Nicotiana occidentalis defensin, NoD173, tomato defensin TPP3 and human β-defensin HBD-3, selectively target tumour cell membranes and rapidly induce the formation of large, irreversible membrane blebs followed by cell lysis. Defensins can prevent tumour cell migration via the disruption
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