Abstract
Increasing evidence highlights the role of bacteria in the physiopathology of cancer. However, the underlying molecular mechanisms remains poorly understood. Several cancer-associated bacteria have been shown to produce toxins which interfere with the host defense against tumorigenesis. Here, we show that lipopolysaccharides from Klebsiella pneumoniae and other Enterobacteria strongly inhibit the host tumor suppressor p53 pathway through a novel mechanism of p53 regulation. We found that lipopolysaccharides destabilize TP53 mRNA through a TLR4-NF-κB-mediated inhibition of the RNA-binding factor Wig-1. Importantly, we show that K. pneumoniae disables two major tumor barriers, oncogene-induced DNA damage signaling and senescence, by impairing p53 transcriptional activity upon DNA damage and oncogenic stress. Furthermore, we found an inverse correlation between the levels of TLR4 and p53 mutation in colorectal tumors. Hence, our data suggest that the repression of p53 by Enterobacteria via TLR4 alleviates the selection pressure for p53 oncogenic mutations and shapes the genomic evolution of cancer.
Highlights
Increasing evidence highlights the role of bacteria in the physiopathology of cancer
We find that lipopolysaccharide (LPS) from K. pneumoniae and other Enterobacteria inhibits p53 through the TLR4-NFκB pathway, and we uncover a novel mechanism of p53 regulation whereby p53 inhibition occurs at the mRNA level
Klebsiella pneumoniae inhibits p53 To investigate the effect of K. pneumoniae on the host p53 pathway, we infected human immortalized fibroblasts (BJ hTERT) with live bacteria
Summary
Increasing evidence highlights the role of bacteria in the physiopathology of cancer. Several cancer-associated bacteria have been shown to produce toxins which interfere with the host defense against tumorigenesis. We show that lipopolysaccharides from Klebsiella pneumoniae and other Enterobacteria strongly inhibit the host tumor suppressor p53 pathway through a novel mechanism of p53 regulation. Known oncogenic bacteria such as H. pylori [12–14], Chlamydia trachomatis [15] and several Mycoplasma species [16] interfere with the p53 pathway. These studies suggest that p53 inactivation could be a more general hallmark of microbes with tumorigenic potential. We find that lipopolysaccharide (LPS) from K. pneumoniae and other Enterobacteria inhibits p53 through the TLR4-NFκB pathway, and we uncover a novel mechanism of p53 regulation whereby p53 inhibition occurs at the mRNA level. IFNγ-mediated signaling pathway response to type I interferon regulaƟon of apoptoƟc signaling pathway cellular response to type I interferon type I interferon signaling pathway extrinsic apoptoƟc signalig pathway
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