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PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-β pathway
Haibo Wang1,2,3, Lijie Zhang4, Hua Liu1
1Beijing Key Laboratory for Tumor Invasion and Metastasis, Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, People's Republic of China.
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.
Insights
PDZK1 downregulation contributes to sunitinib resistance in clear cell renal cell carcinoma (ccRCC). Upregulating PDZK1 via miR-15b antagomirs may overcome this resistance, offering a new therapeutic strategy for ccRCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Sunitinib is a primary treatment for advanced clear cell renal cell carcinoma (ccRCC).
- Drug resistance and adverse effects limit sunitinib's clinical efficacy in ccRCC.
- Understanding mechanisms of sunitinib resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate differentially expressed genes related to sunitinib sensitivity and resistance in ccRCC.
- To explore the role and molecular mechanism of PDZK1 in ccRCC.
- To identify potential therapeutic targets for overcoming sunitinib resistance in ccRCC.
Main Methods:
- Investigated differentially expressed genes (DEGs) in ccRCC.
- Utilized cell counting kit-8, colony formation, flow cytometry, and xenograft models.
- Performed western blot, co-immunoprecipitation, immunofluorescence, and immunohistochemistry.
Main Results:
- PDZK1 is downregulated in sunitinib-resistant ccRCC specimens.
- PDZK1 negatively regulates PDGFR-β phosphorylation and downstream signaling.
- Low PDZK1 levels promote cell proliferation and tumor growth, leading to sunitinib insensitivity.
- miR-15b antagomirs increased PDZK1 levels, enhancing sunitinib's cytotoxic effects in ccRCC cells.
Conclusions:
- The miR-15b/PDZK1/PDGFR-β axis is a potential therapeutic target for ccRCC.
- This axis may serve as a predictive biomarker for sunitinib treatment response in ccRCC patients.
- Targeting this axis offers a novel strategy to overcome sunitinib resistance in ccRCC.
