Novel role of Stat1 in the development of docetaxel resistance in prostate tumor cells.
A major obstacle for clinicians in the treatment of advanced prostate cancer is the inevitable progression to chemoresistance, especially to docetaxel. It is essential to understand the molecular events that lead to docetaxel resistance in order to identify means to prevent or interfere with chemoresistance. In initial attempts to detect these events, we analysed genomic differences between non-resistant and docetaxel-resistant prostate tumor cells and, of the genes modulated by docetaxel treatment, we observed Stat1 and clusterin gene expression heightened in the resistant phenotype. In this study, we provide biochemical and biological evidence that these two gene products are related. Stat1 and clusterin protein expression was induced upon docetaxel treatment of DU145 cells and highly overexpressed in the docetaxel-resistant DU145 cells (DU145-DR). The increase in total Stat1 corresponded to an increase in phosphorylated Stat1. Interestingly, there was no detectable difference between DU145 and DU145-DR cells expression of total Stat3 and phosphorylated Stat3. Treatment of DU145-DR cells with small interfering RNA targeted for Stat1 not only resulted in the knockdown of Stat1 expression, but it also caused the inhibition of clusterin expression. Thus, Stat1 appears to play a key role in the regulation of clusterin. Remarkably, inhibition of Stat1 or clusterin expression resulted in the re-sensitization of DU145-DR cells to docetaxel. These results offer the first evidence that Stat1, and its subsequent regulation of clusterin, are essential for docetaxel resistance in prostate cancer. Targeting this pathway could be a potential therapeutic means for intervention of docetaxel resistance.
Patterson
S G
SG
Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL, USA.
Wei
S
S
Chen
X
X
Sallman
D A
DA
Gilvary
D L
DL
Zhong
B
B
Pow-Sang
J
J
Yeatman
T
T
Djeu
J Y
JY
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001483:Base Sequence; D002460:Cell Line; D051152:Clusterin / Q000235:genetics; D017931:DNA Primers; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D034741:RNA, Small Interfering / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology*; D043823:Taxoids / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D051152:Clusterin; D017931:DNA Primers; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D043823:Taxoids; D000077143:Docetaxel