2. Academic Validation
  3. PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma

  • Cell Death Dis. 2023 Mar 11;14(3):193. doi: 10.1038/s41419-023-05719-x.
Lichun Kang # 1 2,  Dekun Wang # 1,  Tianyu Shen 1,  Xuan Liu 1,  Bo Dai 1,  Donghui Zhou 1,  Huan Shen 3,  Junbo Gong 3,  Gang Li 4,  Yuanjing Hu 5,  Peng Wang 6,  Xue Mi 1,  Yuying Zhang 1,  Xiaoyue Tan 7
Affiliations

Affiliations

  • 1 Department of Pathology, School of Medicine, Nankai University, Tianjin, China.
  • 2 Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, China.
  • 3 School of Chemical Engineering and technology, Tianjin University, Tianjin, China.
  • 4 Urology Division, The Second Hospital of Tianjin Medical University, Tianjin, China.
  • 5 Department of Gynecologic Oncology, Tianjin Central Hospital of O & G, Tianjin, China.
  • 6 Nankai University Affiliated Eye Hospital, Tianjin, China.
  • 7 Department of Pathology, School of Medicine, Nankai University, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 36906674 DOI: 10.1038/s41419-023-05719-x
Abstract

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced Ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal's effect on Ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to Ferroptosis, while ectopic overexpression of PDIA4 conferred Ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating Ferroptosis. In vivo, the administration of Sal promoted Ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes Ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to Ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

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