Faculty Collaboration Database

p21 Expression by human urothelial carcinoma cells modulates the phenotypic response to BCG. Urol Oncol 2010;28(5):526-33

Date

05/20/2009

Pubmed ID

19450997

DOI

10.1016/j.urolonc.2008.12.023

Scopus ID

2-s2.0-77956284009 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

PURPOSE: The direct phenotypic effects of BCG on human urothelial carcinoma (UC) cells include cell cycle arrest, apoptotic resistance, and caspase-independent cell death. These effects are associated with increased expression of the cyclin dependant kinase inhibitor (CDKI) p21. This study assessed the role of p21 expression in mediating the phenotypic effects observed in response to BCG.

MATERIALS AND METHODS: Inducible systems for the autocrine expression of p21, or the blockade of p21 expression in response to BCG, were established in the human UC line T24. The effect of increasing or inhibiting p21 expression on tumor phenotype was assessed using assays for cell cycle compartmentalization (flow cytometry), apoptotic sensitivity (caspase 3 activation), and cytotoxicity (vital dye exclusion).

RESULTS: p21 Overexpression resulted in cell cycle arrest with an increase in the percentage of the cell in G0/G1 phase when compared with the untreated group. p21 Expression decreased basal caspase-3 expression compared with the untreated group, and reversed camptothecin-induced caspase-3 activity compared with camptothecin alone group. p21 Overexpression increased BCG's direct cytotoxicity. shRNA-mediated inhibition of p21 expression in response to BCG failed to reverse BCG-induced changes in cell cycle compartmentalization. p21 Inhibition partially reversed the antiapoptotic effect of BCG. The expression of p21 was required for the direct cytotoxic effect of BCG.

CONCLUSIONS: p21 Expression is sufficient but not necessary for BCG-induced cell cycle arrest. It is both sufficient and necessary for the full antiapoptotic effect of BCG. p21 Expression alone is not sufficient for caspase-independent cytotoxicity but is necessary for BCG's direct cytotoxic effect.

Author List

See WA, Zhang G, Chen F, Cao Y

Author

William See MD Emeritus Professor in the Urology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

BCG Vaccine
Camptothecin
Caspase 3
Cell Cycle
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21
Ecdysterone
Humans
Phenotype
Urinary Bladder Neoplasms