Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs

Oncotarget. 2016 May 3;7(18):26496-515. doi: 10.18632/oncotarget.8420.


Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.

Keywords: DNA damage; RIG-I-like receptor (RLR); Type I interferon; ionizing radiation; small non-coding RNAs.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DEAD Box Protein 58 / drug effects*
  • DEAD Box Protein 58 / metabolism*
  • DEAD Box Protein 58 / radiation effects*
  • Humans
  • Interferon-beta / biosynthesis*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / metabolism*
  • Neoplasms / therapy
  • RNA, Small Untranslated / drug effects
  • RNA, Small Untranslated / metabolism
  • RNA, Small Untranslated / radiation effects
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects


  • RNA, Small Untranslated
  • Interferon-beta
  • DEAD Box Protein 58