Abstract 4849
Background
Endoplasmic reticulum (ER) stress-induced, unfolded protein response (UPR)-mediated apoptosis is a protective mechanism whose failure contributes to malignant tumor progression. XAF1 is a stress-inducible, pro-apoptotic tumor suppressor which is inactivated in many human tumor cells. The molecular signal mechanism explaining its function in controlling ER stress, however, remains largely unclear. In this study, we explored the role of XAF1 in UPR signaling and ER stress-induced apoptosis.
Methods
XAF1 and GRP78 expression were determined by RT-PCR and immunoblot assay. the interplay of XAF1 with GRP78 was defined using immunoprecipitation and in vitro pull-down assays. ER stress was induced using thapsigargin, tunicamycin and brefeldin A. Flow cytometry was used to assess cell cycle progression and apoptosis.
Results
XAF1 expression is upregulated at the transcriptional level in response to ER stress and this activation is abolished by suppression of PERK-Nrf2 but not of IRE1a or ATF6 signaling. This indicates that XAF1 is a target of Nrf2 in transcriptional level and activated by ER stress through the PERK pathway. This XAF1 induction greatly enhances the apoptotic response of tumor cells to ER stress while blockade of XAF1 induction reduces apoptotic sensitivity of tumor cells to ER stress. Intriguingly, XAF1 decreases the protein level of the ER stress sensor, GRP78, and consequently activates UPR signaling. Mechanistically, XAF1 binds directly to GRP78 and stimulates its proteasomal degradation in an E3 ligase ZNF313-dependent manner. XAF1 facilitates ZNF313 interaction with GRP78 and thereby promoting ZNF313-mediated K48 ubiquitination of GRP78. Unlikely wild-type XAF1, mutant XAF1 lacking GRP78- or ZNF313-binding domain shows no activity to promote ER stress-induced apoptosis.
Conclusions
Conclusion: XAF1 sensitizes cells to ER stress and drives apoptotic switch of UPR function away from cell cycle arrest by directly antagonizing GRP78 through the assembly of a ZNF313-mediated destruction complex. Our study identifies first a cell-fate decisions function of XAF1 under ER stress conditions.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Sung-Gil Chi.
Funding
BK.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2273 - High performance of serial tumor biopsies in first in human (FIH) phase I trials.
Presenter: Jun Sato
Session: Poster Display session 1
Resources:
Abstract
5933 - Response rates and lesion-level progression patterns of solid tumor patients in an academic phase 1 program: implications for tumor heterogeneity
Presenter: Christopher Chen
Session: Poster Display session 1
Resources:
Abstract
3569 - Clinical Benefit and Response Rate in Early Phase Clinical Trials: First Report from a Single-Institution Study
Presenter: Antonio Marra
Session: Poster Display session 1
Resources:
Abstract
4139 - Patient (pt) selection for immunotherapeutic early-phase clinical trials (ieCTs): a single Phase I Unit experience
Presenter: Matteo Simonelli
Session: Poster Display session 1
Resources:
Abstract
4451 - Improving patient selection for immuno-oncology phase 1 trials: an external validation of five prognostic scores at Claudius Regaud Institute of Toulouse, Oncopôle (IUCT-O).
Presenter: Ghassan Al Darazi
Session: Poster Display session 1
Resources:
Abstract
1696 - Demonstrating the Changing Trends in Phase 1 Clinical Trials
Presenter: Christina Guo
Session: Poster Display session 1
Resources:
Abstract
3202 - Participation of Women in phase 1 oncology clinical trials
Presenter: Laura Vidal
Session: Poster Display session 1
Resources:
Abstract
4518 - Predictors for early trial discontinuation of patients with cancer participating in phase I clinical trials
Presenter: Joeri Douma
Session: Poster Display session 1
Resources:
Abstract
4368 - Safety of Tumor Treating Fields delivery to the torso: Meta analysis from TTFields clinical trials
Presenter: Federica Grosso
Session: Poster Display session 1
Resources:
Abstract
4615 - Proteomic Profiling Identifies Molecular Basis of Adverse Event to BPM31510 Exposure: Rationale for Comprehensive Molecular Pharmacodynamics (PD) in Phase 1 Clinical Trial Design
Presenter: Vivek Subbiah
Session: Poster Display session 1
Resources:
Abstract