Deciphering the oncogenic influence of Pasteurella multocida: Implications of matrix metalloproteinase activation

Pathogenic bacteria exploit host cells by interfering with the signalling pathways in several ways. <i>Pasteurella multocida</i>, a gram-negative coccobacillus, occurs as a commensal in humans and animals and causes various diseases in ungulates by surviving inside the host cells. <i>P. multocida</i> toxin (PMT) was reported to be one of the most potent mitogens that possess tumour-promoting properties. The present study examined the mitogenic potential of <i>P. multocida</i> cell lysate and culture supernatant on fibrosarcoma cells (HT1080). Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9) activity were significantly induced in the presence of <i>P. multocida</i> cell lysate, culture supernatant and in co-culture conditions. Downregulation of endogenous inhibitors of MMP like Tissue Inhibitor of Metalloproteinases (TIMP-2) and reversion inducing cysteine rich protein with kazal motifs (RECK) was also observed. Significant induction of mitogenic and cell survival pathways like p44/42MAPK and Akt was observed in the presence of bacterial components. A pronounced increase in migration and invasion of HT1080 was observed with bacterial cell lysate and culture supernatant. Treatment with plumbagin, a natural naphthoquinone from the medicinal plant <i>Plumbago zeylanica,</i> demonstrated significant cell death in HT1080. In the presence of culture supernatant and cell lysate of <i>P. multocida</i>, the cell death induced by plumbagin was reduced indicating the role of the bacterial components in promoting the proliferation of cells. Therefore, the present study confirms the role of bacterial infections in promoting the proliferation of cancer cells or worsening existing cancers, thereby emphasizing the need for novel perspectives in developing therapies to combat such infections effectively.