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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma
Matilde Simoni1, Chiara Menegazzi1, Cristina Fracassi1
1Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Abstract:
Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.
Insights
Clear-cell renal cell carcinoma (ccRCC) cells depend on the promyelocytic leukemia (PML) protein. Inhibiting PML restores p53 function, halts ccRCC growth, and improves therapy response.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Clear-cell renal cell carcinoma (ccRCC) has poor survival rates, often diagnosed at advanced stages.
- Therapy resistance in ccRCC is linked to p53 protein malfunction, with mechanisms poorly understood.
- Identifying novel therapeutic targets is crucial for improving ccRCC patient outcomes.
Purpose of the Study:
- To investigate the role of the promyelocytic leukemia (PML) protein in ccRCC progression and therapy resistance.
- To elucidate the mechanistic link between PML, p53, and cellular senescence in ccRCC.
- To evaluate the therapeutic potential of targeting PML in ccRCC.
Main Methods:
- Analysis of PML protein expression in ccRCC tissues.
- In vitro and in vivo studies involving PML depletion in ccRCC cells.
- Investigation of p53 activity and cellular senescence following PML manipulation.
- Treatment of ccRCC models with arsenic trioxide, an FDA-approved PML inhibitor.
Main Results:
- PML protein is overexpressed in ccRCC.
- PML depletion inhibits ccRCC cell proliferation and reduces tumor aggressiveness in vivo.
- PML loss reactivates p53-dependent cellular senescence, a novel regulatory axis in ccRCC.
- Arsenic trioxide treatment degrades PML, increases p53 levels, and suppresses ccRCC growth.
Conclusions:
- ccRCC exhibits a non-oncogene addiction to PML.
- Targeting PML represents a novel therapeutic vulnerability in ccRCC.
- Repurposing arsenic trioxide can restore p53 function and enhance chemosensitivity in ccRCC.
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