IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling

Nat Commun. 2019 Jan 24;10(1):323. doi: 10.1038/s41467-018-08152-3.

Abstract

Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Benzopyrans / therapeutic use
  • Cell Line, Tumor
  • Cell Survival
  • Endoribonucleases / antagonists & inhibitors
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Morpholines / chemistry
  • Morpholines / pharmacology*
  • Morpholines / therapeutic use
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Random Allocation
  • Signal Transduction / physiology*
  • X-Box Binding Protein 1 / metabolism*

Substances

  • Antineoplastic Agents
  • Benzopyrans
  • MKC8866
  • MYC protein, human
  • Morpholines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • X-Box Binding Protein 1
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases