School of Life Sciences, Canterbury Christ Church University, Canterbury, United Kingdom.
PLoS One. 2021 Sep 2;16(9):e0251951. doi: 10.1371/journal.pone.0251951. eCollection 2021.
The purpose of this study was to explore potential mechanisms of cytotoxicity towards HeLa and HT29 cells displayed by Pediocin PA-1. We did this by carrying out sequence alignments and 3D modelling of related bacteriocins which have been studied in greater detail: Microcin E492, Enterocin AB heterodimer and Divercin V41. Microcin E492 interacts with Toll-Like Receptor 4 in order to activate an apoptosis reaction, sequence alignment showed a high homology between Pediocin PA-1 and Microcin E492 whereas 3D modelling showed Pediocin PA-1 interacting with TLR-4 in a way reminiscent of Microcin E492. Furthermore, Pediocin PA-1 had the highest homology with the Enterocin heterodimer, particularly chain A; Enterocin has also shown to cause an apoptotic response in cancer cells. Based on this we are led to strongly believe Pediocin PA-1 interacts with TLRs in order to cause cell death. If this is the case, it would explain the difference in cytotoxicity towards HeLa over HT29 cells, due to difference in expression of particular TLRs. Overall, we believe Pediocin PA-1 exhibits a dual effect which is dose dependant, like that of Microcin. Unfortunately, due to the COVID-19 pandemic, we were unable to carry out experiments in the lab, and the unavailability of important data meant we were unable to provide and validate out solid conclusions, but rather suggestions. However, bioinformatic analysis is still able to provide information regarding structure and sequence analysis to draw plausible and evidence based conclusions. We have been able to highlight interesting findings and how these could be translated into future research and therapeutics in order to improve the quality of treatment and life of cancer patients.
本研究旨在探索肠球菌素 PA-1 对 HeLa 和 HT29 细胞产生细胞毒性的潜在机制。我们通过对已进行更详细研究的相关细菌素进行序列比对和 3D 建模来实现这一目标：微菌素 E492、肠球菌 AB 异二聚体和 divercin V41。微菌素 E492 通过与 Toll 样受体 4 相互作用来激活细胞凋亡反应，序列比对显示肠球菌素 PA-1 与微菌素 E492 具有高度同源性，而 3D 建模显示肠球菌素 PA-1 与 TLR-4 相互作用的方式类似于微菌素 E492。此外，肠球菌素 PA-1 与肠球菌异二聚体具有最高的同源性，特别是链 A；肠球菌也已显示在癌细胞中引起凋亡反应。基于此，我们强烈认为肠球菌素 PA-1 通过与 TLR 相互作用来导致细胞死亡。如果是这样，这将解释它对 HeLa 细胞的细胞毒性与 HT29 细胞的差异，这是由于特定 TLR 表达的差异。总的来说，我们相信肠球菌素 PA-1 表现出一种双重作用，这种作用是剂量依赖性的，类似于微菌素的作用。不幸的是，由于 COVID-19 大流行，我们无法在实验室进行实验，并且由于缺乏重要数据，我们无法提供和验证我们的可靠结论，而只是提供建议。然而，生物信息学分析仍然能够提供有关结构和序列分析的信息，以得出合理和基于证据的结论。我们已经能够强调有趣的发现，以及如何将这些发现转化为未来的研究和治疗方法，以提高癌症患者的治疗质量和生活质量。
