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PTPRZ1 dephosphorylates and stabilizes RNF26 to reduce the efficacy of TKIs and PD-1 blockade in ccRCC

Oncogene volume 43, pages 3633–3644 (2024)Cite this article

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Abstract

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often exhibits resistance to tyrosine kinase inhibitors (TKIs) when used as monotherapy. However, the integration of PD-1 blockade with TKIs has significantly improved patient survival, making it a leading therapeutic strategy for ccRCC. Despite these advancements, the efficacy of this combined therapy remains suboptimal, necessitating a deeper understanding of the underlying regulatory mechanisms. Through comprehensive analyses, including mass spectrometry, RNA sequencing, lipidomic profiling, immunohistochemical staining, and ex vivo experiments, we explored the interaction between PTPRZ1 and RNF26 and its impact on ccRCC cell behavior. Our results revealed a unique interaction where PTPRZ1 stabilized RNF26 protein expression by dephosphorylating it at the Y432 site. The modulation of RNF26 levels by PTPRZ1 was found to be mediated through the proteasome pathway. Additionally, PTPRZ1, via its interaction with RNF26, activated the TNF/NF-κB signaling pathway, thereby promoting cell proliferation, angiogenesis, and lipid metabolism in ccRCC cells. Importantly, inhibiting PTPRZ1 enhanced the sensitivity of ccRCC to TKIs and PD-1 blockade, an effect that was attenuated when RNF26 was simultaneously knocked down. These findings highlight the critical role of the PTPRZ1-RNF26 axis in ccRCC and suggest that combining PTPRZ1 inhibitors with current TKIs and PD-1 blockade therapies could significantly improve treatment outcomes for ccRCC patients.

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Fig. 1: PTPRZ1 binds to and stablizes RNF26 in ccRCC.
Fig. 2: PTPRZ1 dephosphorylates RNF26 at Y432 site.
Fig. 3: PTPRZ1 contributes to the activation of the TNF and NF-kappa B signaling pathways in ccRCC cells.
Fig. 4: PTPRZ1 regulates the lipid metabolism of ccRCC cells.
Fig. 5: RNF26 is the key mediator for PTPRZ1 in ccRCC.
Fig. 6: PTPRZ1 decreases the anti-tumor effect of ccRCC to TKIs and PD-1 blockade.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

We would like to thank ProMab Biotechnologies, Inc. (Changsha, China) for their support with western blotting. Our schematic diagrams were created with BioRender.com.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82203537 (Wentao Liu)).

Author information

Author notes

  1. These authors contributed equally: Yongkang Ma, Wei Li, Xinlin Liu.

Authors and Affiliations

  1. Department of Urology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China

    Yongkang Ma

  2. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China

    Wei Li, Xinlin Liu & Wentao Liu

  3. Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China

    Wei Li, Xinlin Liu & Wentao Liu

  4. Hunan Engineering Research Center of Smart and Precise Medicine, Changsha, Hunan, 410011, China

    Wei Li, Xinlin Liu & Wentao Liu

  5. Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

    Weilin Peng & Bei Qing

  6. Robotic Minimally Invasive Surgery Center, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Shangqing Ren

  7. Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan Province, China

    Xiaobing Chen

  8. State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, China

    Xiaobing Chen

  9. Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou, Henan Province, China

    Xiaobing Chen

  10. Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou, Henan Province, China

    Xiaobing Chen

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  1. Yongkang Ma
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Contributions

Yongkang Ma: Methodology; Wei Li: Methodology; Xinlin Liu: Methodology; Weilin Peng: Formal analysis; Bei Qing: Formal analysis; Shangqing Ren: Project administration; Wentao Liu: Methodology, Investigation; Xiaobing Chen: Project administration, Investigation.

Corresponding authors

Correspondence to Shangqing Ren, Wentao Liu or Xiaobing Chen.

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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. It was approved by the Animal Use and Care Committees at the Second Xiangya hospital, Central South University.

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Ma, Y., Li, W., Liu, X. et al. PTPRZ1 dephosphorylates and stabilizes RNF26 to reduce the efficacy of TKIs and PD-1 blockade in ccRCC. Oncogene 43, 3633–3644 (2024). https://doi.org/10.1038/s41388-024-03198-8

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