ETS1 promotes chemoresistance and invasion of paclitaxel-resistant, hormone-refractory PC3 prostate cancer cells by up-regulating MDR1 and MMP9 expression.
ETS1, which belongs to the ETS transcription factor family, plays important roles in diverse aspects of cancer such as drug resistance and metastasis. In the present study, we examined the functional roles of ETS1 in paclitaxel resistance and invasion using human prostate cancer PC3 cells and paclitaxel-resistant PC3PR cells established from PC3 cells. Our results showed that ETS1mRNA and protein expression was markedly up-regulated in paclitaxel-resistant PC3PR cells compared with paclitaxel-sensitive PC3 cells. The mRNA levels of MDR1 as well as MMP1, MMP3, MMP9 and uPA were positively correlated with that of ETS1. In PC3PR cells, silencing of ETS1 expression by siRNAs inhibited the activity of the MDR1 promoter containing ETS binding sites, reduced the mRNA and protein levels of MDR1 and suppressed paclitaxel resistance. Furthermore, ETS1 knockdown decreased secretion of MMP9 as well as its intracellular mRNA level, and dramatically inhibited invasion of PC3PR cells. Our results suggest that ETS1 promotes paclitaxel resistance and invasion in part by up-regulating MDR1 and MMP9 expression. Taken together, a novel therapeutic strategy targeting the ETS1 gene could be designed to overcome chemoresistance and metastasis of taxane-resistant, hormone-refractory prostate cancer.
Department of Urology, Gifu University Graduate School of Medicine, Japan.
Taku
T
Kato
Yasunori
Y
Fujita
Keita
K
Nakane
Toshio
T
Kojima
Yoshinori
Y
Nozawa
Takashi
T
Deguchi
Masafumi
M
Ito
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D050784:Proto-Oncogene Protein c-ets-1 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; C494041:ETS1 protein, human; D061965:Matrix Metalloproteinase Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; D020780:Matrix Metalloproteinase 9; D017239:Paclitaxel