Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling
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Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling. / Qu, Yi; Oyan, Anne Margrete; Liu, Runhui; Hua, Yaping; Zhang, Jigang; Hovland, Randi; Popa, Mihaela; Liu, Xiaojun; Brokstad, Karl A; Simon, Ronald; Molven, Anders; Lin, Biaoyang; Zhang, Wei-dong; McCormack, Emmet; Kalland, Karl-Henning; Ke, Xi-Song.
In: CANCER RES, Vol. 73, No. 23, 01.12.2013, p. 7090-100.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling
AU - Qu, Yi
AU - Oyan, Anne Margrete
AU - Liu, Runhui
AU - Hua, Yaping
AU - Zhang, Jigang
AU - Hovland, Randi
AU - Popa, Mihaela
AU - Liu, Xiaojun
AU - Brokstad, Karl A
AU - Simon, Ronald
AU - Molven, Anders
AU - Lin, Biaoyang
AU - Zhang, Wei-dong
AU - McCormack, Emmet
AU - Kalland, Karl-Henning
AU - Ke, Xi-Song
PY - 2013/12/1
Y1 - 2013/12/1
N2 - How prostate cancer is initiated remains a topic of debate. In an effort to establish a human model of prostate carcinogenesis, we adapted premalignant human prostate EPT2-D5 cells to protein-free medium to generate numerous tight prostate spheres (D5HS) in monolayer culture. In contrast to EPT2-D5 cells, the newly generated D5HS efficiently formed large subcutaneous tumors and subsequent metastases in vivo, showing the tumorigenicity of D5HS spheres. A striking production of interleukin (IL)-6 mRNA and protein was found in D5HS cells. The essential roles of IL-6 and the downstream STAT3 signaling in D5HS tumor sphere formation were confirmed by neutralizing antibody, chemical inhibitors, and fluorescent pathway reporter. In addition, elevated reactive oxygen species (ROS) produced upon protein depletion was required for the activation of IL-6/STAT3 in D5HS. Importantly, a positive feedback loop was found between ROS and IL-6 during tumor sphere formation. The association of ROS/IL-6/STAT3 to the carcinogenesis of human prostate cells was further examined in xenograft tumors and verified by limiting dilution implantations. Collectively, we have for the first time established human prostate tumor-initiating cells based on physiologic adaption. The intrinsic association of ROS and IL-6/STAT3 signaling in human prostate carcinogenesis shed new light on this relationship and define therapeutic targets in this setting.
AB - How prostate cancer is initiated remains a topic of debate. In an effort to establish a human model of prostate carcinogenesis, we adapted premalignant human prostate EPT2-D5 cells to protein-free medium to generate numerous tight prostate spheres (D5HS) in monolayer culture. In contrast to EPT2-D5 cells, the newly generated D5HS efficiently formed large subcutaneous tumors and subsequent metastases in vivo, showing the tumorigenicity of D5HS spheres. A striking production of interleukin (IL)-6 mRNA and protein was found in D5HS cells. The essential roles of IL-6 and the downstream STAT3 signaling in D5HS tumor sphere formation were confirmed by neutralizing antibody, chemical inhibitors, and fluorescent pathway reporter. In addition, elevated reactive oxygen species (ROS) produced upon protein depletion was required for the activation of IL-6/STAT3 in D5HS. Importantly, a positive feedback loop was found between ROS and IL-6 during tumor sphere formation. The association of ROS/IL-6/STAT3 to the carcinogenesis of human prostate cells was further examined in xenograft tumors and verified by limiting dilution implantations. Collectively, we have for the first time established human prostate tumor-initiating cells based on physiologic adaption. The intrinsic association of ROS and IL-6/STAT3 signaling in human prostate carcinogenesis shed new light on this relationship and define therapeutic targets in this setting.
KW - Animals
KW - Cell Proliferation
KW - Humans
KW - Interleukin-6
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Nude
KW - Mice, Transgenic
KW - Neoplastic Stem Cells
KW - Prostatic Neoplasms
KW - Reactive Oxygen Species
KW - STAT3 Transcription Factor
KW - Signal Transduction
KW - Spheroids, Cellular
KW - Tumor Cells, Cultured
U2 - 10.1158/0008-5472.CAN-13-1560
DO - 10.1158/0008-5472.CAN-13-1560
M3 - SCORING: Journal article
C2 - 24101153
VL - 73
SP - 7090
EP - 7100
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 23
ER -