Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Abstract

Bladder pathologies, very common in the aged population, have a considerable negative impact on quality of life. Novel targets are needed to design drugs and combinations to treat diseases such as overactive bladder and bladder cancers. A promising new target is the ubiquitous Rho GTPase Rac1, frequently dysregulated and overexpressed in bladder pathologies. We have analyzed the roles of Rac1 in different bladder pathologies, including bacterial infections, diabetes-induced bladder dysfunctions and bladder cancers. The contribution of the Rac1 protein to tumorigenesis, tumor progression, epithelial-mesenchymal transition of bladder cancer cells and their metastasis has been analyzed. Small molecules selectively targeting Rac1 have been discovered or designed, and two of them—NSC23766 and EHT 1864—have revealed activities against bladder cancer. Their mode of interaction with Rac1, at the GTP binding site or the guanine nucleotide exchange factors (GEF) interaction site, is discussed. Our analysis underlines the possibility of targeting Rac1 with small molecules with the objective to combat bladder dysfunctions and to reduce lower urinary tract symptoms. Finally, the interest of a Rac1 inhibitor to treat advanced chemoresistance prostate cancer, while reducing the risk of associated bladder dysfunction, is discussed. There is hope for a better management of bladder pathologies via Rac1-targeted approaches.

Integrated Pan-Cancer Profiling of RAC1: Prognostic, Immunomodulatory, and Therapeutic Resistance Insights

“…This study conducted a comprehensive analysis of the expression patterns of RAC1 at the pan-cancer level and its relationship with cancer progression, prognosis, immune microenvironment, and drug sensitivity. Our findings echo previous studies that have revealed the important role of RAC1 in various cancers, particularly in regulating cell migration, proliferation and survival 5,[30][31][32] . Furthermore, our research extends the understanding of RAC1 as a prognostic biomarker, further revealing that high expression of RAC1 is associated with reduced B cell infiltration.…”

“…Rac1 is commonly characterized by its heightened expression and/or enhanced activity in a spectrum of solid malignancies, such as bladder 5 , and hepatocellular carcinomas 6 . At the same time, RAC1 is also closely related to tumour metastasis 7 .…”

Extracellular Microvesicles Modified with Arginine-Rich Peptides for Active Macropinocytosis Induction and Delivery of Therapeutic Molecules

“…High expression of EGFR has been observed in human tumors (e.g., the lung and pancreas) associated with a poor prognosis. EGFR activation leads to the induction of the small GTPase Rac1-GTP form in the cytosol, causing actin organization, lamellipodia extensions, and macropinocytotic cellular uptake. ,,− In this study, human epidermoid carcinoma-derived A431 cells with high EGFR expression on the plasma membrane (∼10 6 receptors/cell) , were used for assessing macropinocytosis induction and cellular MV uptake.…”