Bacterial infection-mediated anticancer activity (BIMAc) – Revisiting the molecular mechanisms

Abstract

The anticancer activity demonstrated by genetically attenuated invasive Shigella flexneri contradicts the long-held understanding of bacterial infection-mediated anticancer activity (BIMAc), as a ‘by-stander effect’ caused by an immune response against any invading pathogen as a reason for tumour regression. Similarly, the selective tumouricidal effect by Salmonella A1 auxotrophic mutant in nude mice is another observation where the current theory fails. Considering these flaws, we set to re-examine the mechanisms behind BIMAc independent of immune response, on the basis of molecular understanding about the initial colonisation of gut epithelium by S. flexneri and its production of cell-cycle-inhibiting proteins called cyclomodulins. During infection, S. flexneri injects OspE effector protein into the gut epithelium. The resulting interaction of OspE with ILK prevents epithelial cell exfoliation and facilitates the pathogen’s colonisation of the gut. This interaction is also shown to enhance membrane retention of ILK in these infected cells. Correspondingly, another study reports the indispensable role of ILK in survival of cancer cells with supernumerary centrosomes by localising it to the centrosomes and clustering them into a bipolar spindle. Knockdown of ILK in these cells leads to apoptosis due to multipolar mitosis. From these cumulative facts we hypothesised that enhanced membrane retention of ILK in Shigella-infected cancer cells prevents localisation of ILK to centrosomes and provokes multipolar mitosis and therefore cell death in cancer subpopulations with supernumerary centrosomes. This interaction may also be metastasis suppressive, because of its inhibitory effect on the focal adhesion turnover of gut epithelium, which is quintessential for any form of cell migration. Apart from these, Shigella also encodes potent cell-cycle-inhibiting effector molecules such as cyclomodulins. The additive action of these cyclomodulins along with the OspE–ILK interaction may be considered as the reason behind the anticancer activity mediated by Shigella infection.