Inactivation of AR activates HGF/c-Met system in human prostatic carcinoma cells.
Clinical studies with prostate cancer tissue indicate that alterations in androgen receptor (AR) or c-Met overexpression are associated with androgen-independent progression. We investigated the interaction between AR and c-Met signaling in human prostate cancer cells. Androgen withdrawal or AR-specific small interfering RNA significantly reduced the growth rate while each maneuver induced the expression of c-Met. Knockdown of both AR and c-Met expression markedly inhibited the cell growth. Furthermore, microarray analysis indicated that the activation of c-Met down-regulated the expression of DNA repair-related genes including 8-oxoguanine DNA glycosylase. Exogenous hepatocyte growth factor also induced the production of intracellular reactive oxygen species and resulted in the accumulation of DNA damages. These results suggested that the activation of c-Met signaling may lead to induction of spontaneous mutations or genomic instability, which may lead to the progression of androgen-independent state. Thus, c-Met signaling is utilized for survival and growth under the androgen-depleted condition.
Maeda
Akinobu
A
Department of Urology, Organ Function Integrative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.
Nakashiro
Koh-ichi
K
Hara
Shingo
S
Sasaki
Toyokazu
T
Miwa
Yoshihiro
Y
Tanji
Nozomu
N
Yokoyama
Masayoshi
M
Hamakawa
Hiroyuki
H
Oyasu
Ryoichi
R
D045744:Cell Line, Tumor; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D048049:Extracellular Signal-Regulated MAP Kinases