MyD88 in DNA Repair and Cancer Cell Resistance to Genotoxic Drugs

To ensure recognition of a broad variety of pathogens, the innate immune system has evolved, through a number of receptors, a strategy to recognize a limited number of conserved pathogen-associated molecular patterns. These receptors include the Toll-like receptors (TLRs), which are transmembrane receptors expressed in a variety of immune, but also epithelial and transformed cells (1). TLRs are connected to the cell signaling machinery via intracellular adaptor molecules. The first such adaptor molecule to be discovered was MyD88, which has an N-terminal death domain (DD), which recruits downstream signaling molecules (2). MyD88 is also an adaptor of the interleukin 1 receptor (IL-1R) family signaling. Activation of the TLR/IL-1R signaling pathway activates the major inflammatory transcription factor NF-kB by allowing its nuclear translocation. Inflammation is recognized as a promoter of carcinogenesis (3). Predictably, MyD88 was shown to play a role in tumorigenesis via TLR and IL-1 proinflammatory mechanisms (4). We have recently shown that MyD88 operates as an adaptor connecting inflammatory signaling pathways with the Ras oncogenic signaling pathway. Specifically, we showed that MyD88 is required for Ras-dependent cell signaling and transformation (5). Here we show in a panel of Ras-dependent colon cancer cell lines that, in addition to its role in tumor initiation, MyD88 plays an important role in the survival of Ras-transformed cells. We demonstrate that MyD88 is required for the expression of the major DNA repair enzyme ERCC1, and therefore for efficient DNA repair, and that knocking down MyD88 sensitizes colon cancer cells to genotoxic agents such as platinum salts in vitro and in vivo. These results indicate a novel and original link between inflammation, DNA repair, and cancer.