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Translational Therapeutics

PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-β pathway

Abstract

Background

Sunitinib has emerged as the primary treatment for advanced or metastatic clear cell renal cell carcinoma (ccRCC) due to its significant improvement in patients’ average survival time. However, drug resistance and adverse effects of sunitinib pose challenges to its clinical benefits.

Methods

The differentially expressed genes (DEGs) associated with sunitinib sensitivity and resistance in ccRCC were investigated. Cell counting kit-8, plate colony formation, flow cytometry and subcutaneous xenograft tumor model assays were employed to explore the effects of PDZK1 on ccRCC. Further research on the molecular mechanism was conducted through western blot, co-immunoprecipitation, immunofluorescence co-localization and immunohistochemical staining.

Results

We elucidated that PDZK1 is significantly downregulated in sunitinib-resistant ccRCC specimens, and PDZK1 negatively regulates the phosphorylation of PDGFR-β and the activation of its downstream pathways through interaction with PDGFR-β. The dysregulated low levels of PDZK1 contribute to inadequate inhibition of cell proliferation, tumor growth, and insensitivity to sunitinib treatment. Notably, our preclinical investigations showed that miR-15b antagomirs enhance sunitinib cytotoxic effects against ccRCC cells by upregulating PDZK1 levels, suggesting their potential in overcoming sunitinib resistance.

Conclusions

Our findings establish the miR-15b/PDZK1/PDGFR-β axis as a promising therapeutic target and a novel predictor for ccRCC patients’ response to sunitinib treatment.

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Fig. 1: Dysregulated low levels of PDZK1 in sunitinib-resistant ccRCC.
Fig. 2: PDZK1 specifically associates with PDGFR-β via its carboxyl terminus.
Fig. 3: PDZK1 attenuates PDGFR-β-mediated signaling in ccRCC cells.
Fig. 4: PDZK1 retards ccRCC cell proliferation by suppressing PDGFR-β signaling.
Fig. 5: PDZK1 suppresses ccRCC cell proliferation via PDGFR-β signaling in vivo.
Fig. 6: PDZK1 enhances sunitinib sensitivity by downregulating the PDGFR-β signaling pathway.
Fig. 7: High PDZK1 levels are associated with sunitinib sensitivity and attenuation of PDGFR-β signaling in ccRCC specimens.
Fig. 8: hsa-miR-15b-5p inhibitors synergize with sunitinib in inhibiting ccRCC growth.

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Data availability

The previously published data underlying Figs. 1, 2, 7 and Supplementary Figs. 16 are openly available in [E-MTAB-3267] at [https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-3267]; [GSE64052] at [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64052]; [TCGA, Kidney Renal Clear Cell Carcinoma, PanCancer Atlas] at [https://www.cbioportal.org/study/summary?id=kirc_tcga_pan_can_atlas_2018]; [CPTAC, Clear Cell Renal Cell Carcinoma Discovery Cohort] at [https://pdc.cancer.gov/pdc/study/PDC000128]; [GSE210189] at [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE210189]. The data underlying Fig. 5 (tissue microarrays containing 90 pairs of ccRCC and adjacent tissues) and Fig. 7 (23 human ccRCC samples from the First Hospital of Shanxi Medical University) in this study are not publicly available due to patient privacy issues. However, the data are available from the corresponding author upon reasonable request (for research only).

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Acknowledgements

We would like to thank Doctor Tongmei Zhang (Beijing Chest Hospital, Capital Medical University) and Doctor Jinwei Miao (Beijing Obstetrics and Gynecology Hospital, Capital Medical University) for kindly providing some clinical samples. We thank Dr. Randy Hall at Emory University (Atlanta, GA) and Dr. Michael R Beard at the Centre for Cancer Biology (Adelaide, Australia) for plasmids materials.

Funding

This study was supported by the National Natural Science Foundation of the People’s Republic of China (Grants Nos. 81772707, 81972732, 82273965); China Postdoctoral Foundation (Grants No. 2023M732409). The funding agency did not participate in the study design, data collection, analysis and interpretation, or the writing of this manuscript.

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Conceptualization: JH and HW; data curation: LZ, HL and HW; methodology: HW and LZ; investigation: RS and QQ; validation: XY, DF and SW; visualization: HW and WL; formal analysis: XC and YY; project administration: SW and JH; resources: TB; supervision: JH and TB; funding acquisition: JH and HW; writing—original draft: HL and HW; writing—review & editing: JH and TB.

Corresponding authors

Correspondence to Tao Bai or Junqi He.

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Ethics approval and consent to participate

Animal experiments were conducted in compliance with the National Institutes of Health guidelines for the Care and Use of Laboratory Animals and approved by the Animal Use and Care Committee of Capital Medical University (approval numbers AEEI-2020-133 and AEEI-2018-201). The research involving ccRCC samples was approved by the Ethics Committee of Capital Medical University (2017SY09) and the First Hospital of Shanxi Medical University (2022HLL001).

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Wang, H., Zhang, L., Liu, H. et al. PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-β pathway. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02725-4

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