Genetic disruption of USP9X sensitizes colorectal cancer cells to 5-fluorouracil.
The X-linked deubiquitinase USP9X affects the stability and activity of numerous regulatory proteins that influence cell survival. Recent studies suggest that decreased USP9X expression can confer a selective advantage onto developing cancer cells and thereby promotes disease progression. To examine the effect of USP9X on the cellular responses to anticancer therapies, we derived cancer cell lines in which the USP9X locus was disrupted by homologous recombination. The resulting USP9X-deficient cancer cells exhibited increased activation of apoptotic pathways and markedly decreased clonogenic survival in response to 5-fluorouracil, a chemotherapeutic drug that is widely used for treatment of gastrointestinal malignancies. These unexpected results suggest that cancers with low USP9X expression might be specifically sensitized to some conventional therapeutic agents.
Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Dennis R
DR
Harris
Alexandra
A
Mims
Fred
F
Bunz
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; C506234:USP9X protein, human; D043222:Ubiquitin Thiolesterase; D005472:Fluorouracil