Premium
The Unfolded Protein Response Regulates Pancratic Neuroendocrine Tumor Growth
Author(s) -
Oakes Scott A.,
Qi Jenny Y.,
Moore Paul C,
Warren Rachel A.,
Thamsen Maike,
Ghosh Rajarshi,
Gliedt Micah J.,
Maly Dustin J.,
Backes Bradley J,
Papa Feroz R.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.178.4
Subject(s) - unfolded protein response , biology , endoplasmic reticulum , microbiology and biotechnology , proteostasis , regulator , signal transduction , proteasome , secretory pathway , genetics , gene , golgi apparatus
The Unfolded Protein Response (UPR) is an intracellular signaling pathway that communicates the protein folding status of the endoplasmic reticulum (ER) to the nucleus to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins‐‐conditions often encountered by cancer cells—can lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” However, the precise role of UPR signaling in the development and maintenance of cancer remains controversial. We reasoned that pancreatic neuroendocrine tumors (PanNETs) might be one class of solid tumor that may be particularly sensitive to protein folding stress due to their high secretory activity. The Master UPR regulator IRE1 (Inositol requiring enzyme 1 alpha) is an ER transmembrane kinase/endoribonuclease (RNase) that acts as a critical life‐death switch depending on the level of ER stress. We analyzed primary human PanNET samples for activation of UPR components and found strong evidence of ER stress and IRE1 hyperactivation in this tumor type. We used a variety of chemical‐genetic tools to selectively manipulate IRE1's homeostatic and apoptotic outputs in a PanNET xenograft model and found that the precise balance of IRE1 signaling is critical for tumor growth in vivo . Disrupting this balance by pushing the pathway in either direction is detrimental to PanNET growth and survival. Moreover, targeting IRE1 with highly selective small molecules in a preclinical mouse model phenocopied the results of genetic manipulation. Our results indicate that IRE1 is an important regulator of PanNET cell survival and growth and provide a strong rationale for therapeutically targeting this kinase/RNase in PanNETs and other cancers that experience high levels of ER stress. Support or Funding Information This work was supported by an American Cancer Society Research Scholar Award, American Association for Cancer Research‐Caring for Carcinoid Foundation Award, Harrington Discovery Institute Scholar‐Innovator Award, and the National Institutes of Health: R01CA136577, R01DK095306, U01DK108332.