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Wee1 Inhibition sensitizes prostate cancer cells to Hsp90 inhibitor to activate the intrinsic apoptotic pathway

ABSTRACT: Heat shock protein 90 (Hsp90) is an essential evolutionarily conserved molecular chaperone in eukaryotes. Cancer cells rely on Hsp90 to chaperone activated oncoproteins, and its involvement in numerous signaling pathways makes it an attractive target for drug development. Surprisingly, however, the impact of Hsp90 inhibitors on cancer cells is most commonly cytostatic, and efforts to enhance the anti-tumor activity of Hsp90 inhibitors in the clinic remain a significant challenge. In this study, we show that dual inhibition of Wee1 tyrosine kinase and Hsp90 causes prostate cancer cells to undergo apoptosis. Gene-expression profiling revealed that induction of the intrinsic apoptotic pathway by this drug combination coincided with transcriptional down-regulation of Survivin and Wee1, an outcome not seen in cells treated separately with either agent. At the translational level, expression of these two proteins as well as activated Akt was completely abrogated. Similar results were obtained in prostate cancer xenografts. These data establish a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in prostate cancer, and they provide a mechanistic rationale for stimulating the pro-apoptotic activity of Hsp90 inhibitors. In order to explore the mechanism underlying the enhanced cell death caused by Wee1 inhibitorII and 17-AAG combination, we performed microarray analysis using PC3 cells treated with Wee1 inhibitorII alone, 17-AAG alone, or the two drugs in combination. There are 12 samples in total. There are three experimental replicate. Samples 1, 5 and 9 are control (C) (untreated PC3- prostate cancer cells). Samples 2, 6, and 10 are cells treated with Wee1 inhibitor II (W). Samples 3, 7, and 11 are treated with 17-AAG (A), (an Hsp90 inhibitor). Samples 4, 8, and 12 are treated with both Wee1 inhibitorII and 17-AAG (WA). Samples 5 was removed from our analysis due to weak signal.

ORGANISM(S): Homo sapiens  

SUBMITTER: Soichiro Yoshida   William G Stetler-Stevenson  Alison C Donnelly  Len Neckers  Aki Iwai  Sandra Jensen-Taubman  Naoto Miyajima  Armine K Smith  Brian S Blagg  Xiaolin Wu  Mehdi Mollapour  Dimitra Bourboulia  Sunmin Lee  David Sun  Jane B Trepel  Shinji Tsutsumi 

PROVIDER: E-GEOD-38972 | ArrayExpress | 2013-01-10



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