CCDC6 and USP7 expression levels suggest novel treatment options in high-grade urothelial bladder cancer

Journal of Experimental & Clinical Cancer Research : CR
Francesco MorraAngela Celetti

Abstract

The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing. Deficiency of the tumor suppressor CCDC6 determines PARP-inhibitor sensitivity. The CCDC6 levels are modulated by the deubiquitinase USP7. In this work we scored CCDC6 and USP7 expression levels in primary UBC and we evaluated the expression levels of CCDC6 in correlation with the effects of the PARP-inhibitors combined with the USP7 inhibitor, P5091, in vitro. Since PARP-inhibitors could be enhanced by conventional chemotherapy or DNA damage inducers, we tested the new agent RRx-001, able to induce DNA damage, to prove the benefit of combined treatments in bladder cancer cells. The J82, T24, 5637 and KU-19-19 bladder cancer cells were exposed to USP7 inhibitor P5091 in presence of cycloheximide to analyse the CCDC6 stability. Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays. The ability of the DNA damage inducer RRx-001 to modulate CCDC6 protein levels and H2AX phosphorylation was detected at immunoblot. The combinatio...Continue Reading

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Citations

Mar 9, 2020·Cancer Chemotherapy and Pharmacology·Parthasaradhireddy TanguturiSuresh Ramakrishna
Jun 14, 2020·Cancers·Francesca BufalieriLucia Di Marcotullio
Sep 16, 2020·Journal of Experimental & Clinical Cancer Research : CR·Mingming JinGang Huang
Feb 23, 2019·Journal of Experimental & Clinical Cancer Research : CR·Daniela CriscuoloAngela Celetti
Feb 16, 2021·Frontiers in Oncology·Mei PengXiaoping Yang
Feb 7, 2021·Journal of Experimental & Clinical Cancer Research : CR·Jianchao GeGuowei Shi
Feb 17, 2021·Acta Pharmacologica Sinica·Yi-Xin ChenZhao-Qian Liu
Jan 14, 2022·Laboratory Investigation; a Journal of Technical Methods and Pathology·Chunyan LiuBing Li

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Methods Mentioned

BETA
transfection
FACS
PCR
flow cytometry

Clinical Trials Mentioned

NCT03375307
NCT02452970
NCT02489903
NCT02546661

Software Mentioned

SPSS
TMA dearrayer
QuPath
CompuSyn

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