1. Academic Validation
  2. UAE1 inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer

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

  • Transl Oncol. 2020 Nov;13(11):100834. doi: 10.1016/j.tranon.2020.100834.
Yajing Liu 1 Sahezeel Awadia 1 Amy Delaney 1 Merna Sitto 1 Carl G Engelke 1 Heli Patel 1 Andrew Calcaterra 1 Sylvia Zelenka-Wang 2 Hojin Lee 3 Joseph Contessa 3 Nouri Neamati 4 Mats Ljungman 1 Theodore S Lawrence 1 Meredith A Morgan 1 Alnawaz Rehemtulla 5
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA.
  • 2 Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 5 Department of Radiation Oncology, University of Michigan Medical School and Rogel Cancer Center, Ann Arbor, MI, USA. Electronic address: [email protected].
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 demonstrating antitumor activity at a dose and schedule that did not exhibit obvious normal tissue toxicity. In vitro as well as studies in mouse models failed to show enhanced efficacy when TAK-243 was combined with ionizing radiation or gemcitabine, providing an impetus for future studies to identify agents that synergize with this class of agents for improved tumor control in PDAC. SIGNIFICANCE: The UAE1 inhibitor TAK-243, mediates activation of the unfolded protein response, accumulation of DNA breaks and Apoptosis, providing a rationale for the use as a safe and efficacious anti-cancer therapeutic for PDAC.

Keywords

ER stress; Pancreatic cancer; UAE1 Inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19939S
    98.86%, DNA-PK Inhibitor