gant-61 and Carcinoma--Transitional-Cell

Transitional cell carcinoma (TCC) is the most commonly diagnosed tumor of the canine urinary system. Hedgehog (HH) signaling represents one possible novel therapeutic target, based on its recently identified central role in human urothelial carcinoma. The purpose of this study was to determine if HH mediators are expressed in canine TCC and the effect of inhibition of this pathway on cell growth and survival. HH pathway mediators were found to be expressed in five canine TCC cell lines. Indian HH was expressed in tumor cells in five canine bladder tumor tissues, but not in normal canine bladder tissue. Inhibition of HH signaling with cyclopamine and GANT61 led to significantly decreased cell proliferation but had a smaller effect on apoptosis. These results support future investigation of inhibitors of HH signaling in the treatment of canine TCC.

Topics: Animals; Apoptosis; Carcinoma, Transitional Cell; Cell Line, Tumor; Cell Proliferation; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Polymerase Chain Reaction; Pyridines; Pyrimidines; Urinary Bladder Neoplasms; Veratrum Alkaloids

Hedgehog signaling regulates Gli transcription factors. Aberrant hedgehog signaling can be oncogenic and drugs that block hedgehog are being tested as anticancer agents. We considered whether hedgehog/Gli signaling may be involved in human bladder transitional cell carcinoma proliferative or invasive behavior.. We stratified the human bladder transitional cell carcinoma lines RT4 (ATCC), 253JP, 253BV, UMUC6 and UMUC3 for relative growth rate by cell counting and for in vitro invasiveness by Matrigel invasion assay. Cells were tested for growth inhibition by the hedgehog blocking drug cyclopamine or the inactive mimic tomatidine. Cell RNA was characterized for hedgehog signaling component expression, including ligands, receptors and signaling mediators, by quantitative reverse transcriptase-polymerase chain reaction. Gli2 expression or activity was modified by Gli2 expression lentiviruses or the Gli inhibitor GANT61. We measured effects on proliferation and invasiveness.. Cell growth rates and invasiveness were stratified into an equivalent order (RT4 <243JP <253BV

Topics: Blotting, Western; Carcinoma, Transitional Cell; Cell Line, Tumor; Dioxoles; Gene Expression Profiling; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Linear Models; Neoplasm Invasiveness; Nuclear Proteins; Piperazines; Pyridines; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tomatine; Urinary Bladder Neoplasms; Veratrum Alkaloids; Zinc Finger Protein Gli2