UAE1 inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer

Translational Oncology
Yajing LiuAlnawaz Rehemtulla

Abstract

The Unfolded Protein Response (UPR) plays a key role in the adaptive response to loss of protein homeostasis within the endoplasmic reticulum (ER). The UPR has an adaptive function in protein homeostasis, however, sustained activation of the UPR due to hypoxia, nutrient deprivation, and increased demand for protein synthesis, alters the UPR program such that additional perturbation of ER homeostasis activates a pro-apoptotic program. Since ubiquitination followed by proteasomal degradation of misfolded proteins within the ER is a central mechanism for restoration of ER homeostasis, inhibitors of this pathway have proven to be valuable anti-cancer therapeutics. Ubiquitin activating enzyme 1(UAE1), activates ubiquitin for transfer to target proteins for proteasomal degradation in conjunction with E2 and E3 enzymes. Inhibition of UAE1 activity in response to TAK-243, leads to an accumulation of misfolded proteins within the ER, thereby aggravating ER stress, leading to DNA damage and arrest of cells in the G2/M phase of the cell cycle. Persistent drug treatment mediates a robust induction of apoptosis following a transient cell cycle arrest. These biological effects of TAK-243 were recapitulated in mouse models of PDAC demonstrati...Continue Reading

Datasets Mentioned

BETA
HY-19939S
AZD1775
AZD2281
ABT-888

Methods Mentioned

BETA
protein folding
ubiquitination
PCR
Assay
glycosylation
FACS
xenografts
immunoprecipitation
neddylation

Clinical Trials Mentioned

NCT02045095

Software Mentioned

GraphPad Prism
ImageJ
FlowJo
Comet Assay IV

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