AI Article Synopsis

  • Cancer cells experience stress during growth, and the transcription factor ATF4 helps them adapt by upregulating genes related to stress relief; however, its role in clear cell renal cell carcinoma (ccRCC) was previously unknown.
  • In this study, elevated ATF4 levels in ccRCC tumors correlated with poor patient outcomes, and reducing ATF4 hindered cancer cell growth and invasion by affecting key signaling pathways.
  • The research identified NUPR1 as a crucial target of ATF4 that helps ccRCC cells survive, while targeting ATF4 or using NUPR1 inhibitors enhanced anti-tumor immunity, suggesting new treatment strategies for ccRCC patients.

Article Abstract

Cancer cells encounter unavoidable stress during tumor growth. The stress-induced transcription factor, activating transcription factor 4 (ATF4), has been reported to upregulate various adaptive genes involved in salvage pathways to alleviate stress and promote tumor progression. However, this effect is unknown in clear cell renal cell carcinoma (ccRCC). In this study, we found that ATF4 expression was remarkably upregulated in tumor tissues and associated with poor ccRCC outcomes. ATF4 depletion significantly impaired ccRCC cell proliferation, migration, and invasion in vitro and in vivo by inhibiting the AKT/mTOR and epithelial-mesenchymal transition (EMT)-related signaling pathway. RNA sequencing and functional studies identified nuclear protein 1 (NUPR1) as a key downstream target of ATF4 for repressing ferroptosis and promoting ccRCC cell survival. In addition, targeting ATF4 or pharmacological inhibition using NUPR1 inhibitor ZZW115 promoted antitumor immunity in syngeneic graft mouse models, represented by increased infiltration of CD4 and CD8 T cells. Furthermore, ZZW115 could improve the response to the PD-1 immune checkpoint blockade. The results demonstrate that the ATF4/NUPR1 signaling axis promotes ccRCC survival and facilitates tumor-mediated immunosuppression, providing a set of potential targets and prognostic indicators for ccRCC patients.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528094PMC
http://dx.doi.org/10.1007/s12672-024-01485-0DOI Listing

Publication Analysis

Top Keywords

axis promotes
8
cell survival
8
clear cell
8
cell renal
8
renal cell
8
cell carcinoma
8
transcription factor
8
ccrcc cell
8
cell
7
ccrcc
6

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!