title: MyD88 in DNA repair and cancer cell resistance to genotoxic drugs.
abstract: BACKGROUND
  MyD88 is an adaptor molecule in Toll-like receptor and interleukin 1 receptor signaling implicated in tumorigenesis through proinflammatory mechanisms. We have recently reported that MyD88 also directly promotes optimal activation of the Ras/Erk pathway. Here we investigate MyD88 implication in the maintenance of the transformation of Ras-dependent tumors.
  
  
  METHODS
  RNA interference was used to inhibit MyD88 expression in the colon cancer cell lines HCT116 and LS513. Apoptosis, DNA damage, p53 function, ERCC1 levels, and Ras and inflammatory signaling pathways were analyzed. Using in vitro assays and xenotransplantation in nude mice (five per group), HCT116 tumor growth was assessed following MyD88 knockdown in presence or absence of chemotherapy.
  
  
  RESULTS
  MyD88 exerts antiapoptotic functions in colon cancer cells via the Ras/Erk, but not the NF-κB, pathway. MyD88 inhibition leads to defective ERCC1-dependent DNA repair and to accumulation of DNA damage, resulting in cancer cell death via p53. Furthermore, we show that knocking down MyD88 sensitizes cancer cells to genotoxic agents such as platinum salts in vitro and in vivo. Indeed, HCT116 tumor growth following treatment with a combination of suboptimal MyD88 inhibition and suboptimal doses of cisplatin (fold tumor increase = 5.4 ± 1.6) was statistically significantly reduced in comparison to treatment with doxycycline alone (12.4 ± 3.1) or with cisplatin alone (12.5 ± 2.6) (P = .005 for both, one-sided Student t test).
  
  
  CONCLUSIONS
  Collectively, these results indicate a novel and original link between inflammation, DNA repair, and cancer, and provide further rationale for MyD88 as a potential therapeutic target in Ras-dependent cancers, in the context of concomitant genotoxic chemotherapy.
authors.affiliation: University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Kfoury
authors.forename: Katy
authors.initials: K
authors.lastname: Le Corf
authors.forename: Rana
authors.initials: R
authors.lastname: El Sabeh
authors.forename: Alexandra
authors.initials: A
authors.lastname: Journeaux
authors.forename: Bassam
authors.initials: B
authors.lastname: Badran
authors.forename: Nader
authors.initials: N
authors.lastname: Hussein
authors.forename: Serge
authors.initials: S
authors.lastname: Lebecque
authors.forename: Serge
authors.initials: S
authors.lastname: Manié
authors.forename: Toufic
authors.initials: T
authors.lastname: Renno
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coste
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000032:analysis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D016159:Tumor Suppressor Protein p53; C071447:ERCC1 protein, human; D004720:Endonucleases; D016283:Proto-Oncogene Proteins p21(ras); D004318:Doxycycline; D002945:Cisplatin