TY - JOUR
T1 - Signal transducer and activator of transcription-3 drives the high-fat diet-associated prostate cancer growth
AU - Kwan, Hiu Yee
AU - Liu, Bin
AU - Huang, Chunhua
AU - Fatima, Sarwat
AU - Su, Tao
AU - Zhao, Xiaoshan
AU - Ho, Alan H.M.
AU - Han, Quanbin
AU - Hu, Xianjing
AU - Gong, Rui-Hong
AU - Chen, Minting
AU - Wong, Hoi Leong Xavier
AU - Bian, Zhaoxiang
N1 - Funding Information:
This work was supported by Natural Science Foundation of Guangdong Province #2018A0303130122, GRF HKBU 22103017-ECS, and the Hong Kong Baptist University grants FRG2/17-18/002, FRG2/16-17/010.
Publisher copyright:
© The Author(s) 2019
PY - 2019/9/2
Y1 - 2019/9/2
N2 - Prostate cancer (PCa) is the second leading cause of cancer death in
men. PCa progression can be associated with obesity. Signal transducer
and activator of transcription-3 (STAT3) plays a crucial role in PCa
growth. However, whether STAT3 plays a role in high-fat diet
(HFD)-associated PCa growth is unknown. Our data show that HFD feeding
increases tumor size, STAT3 phosphorylation, and palmitic acid (PA)
level in the xenograft tissues of the PCa-bearing xenograft mouse model.
In vitro studies show that PA increases STAT3 expression and
phosphorylation (STAT3-Y705) in PCa. Computational modeling suggests
strong and stable binding between PA and unphosphorylated STAT3 at R593
and N538. The binding changes STAT3 structure and activity. Functional
studies show that both STAT3 mutants (R583A and N538A) and STAT3
dominant negative significantly reduce PA-enhanced STAT3
phosphorylation, PA-increased PCa cell proliferation, migration, and
invasion. In the xenograft mouse models, the HFD-increased tumor growth
and STAT3 phosphorylation in tumors are reversed by STAT3 inhibition.
Our study not only demonstrates the regulatory role of PA/STAT3 axis in
HFD-associated PCa growth but also suggests a novel mechanism of how
STAT3 is activated by PA. Our data suggest STAT3 as a therapeutic target
for the treatment of HFD-associated PCa.
AB - Prostate cancer (PCa) is the second leading cause of cancer death in
men. PCa progression can be associated with obesity. Signal transducer
and activator of transcription-3 (STAT3) plays a crucial role in PCa
growth. However, whether STAT3 plays a role in high-fat diet
(HFD)-associated PCa growth is unknown. Our data show that HFD feeding
increases tumor size, STAT3 phosphorylation, and palmitic acid (PA)
level in the xenograft tissues of the PCa-bearing xenograft mouse model.
In vitro studies show that PA increases STAT3 expression and
phosphorylation (STAT3-Y705) in PCa. Computational modeling suggests
strong and stable binding between PA and unphosphorylated STAT3 at R593
and N538. The binding changes STAT3 structure and activity. Functional
studies show that both STAT3 mutants (R583A and N538A) and STAT3
dominant negative significantly reduce PA-enhanced STAT3
phosphorylation, PA-increased PCa cell proliferation, migration, and
invasion. In the xenograft mouse models, the HFD-increased tumor growth
and STAT3 phosphorylation in tumors are reversed by STAT3 inhibition.
Our study not only demonstrates the regulatory role of PA/STAT3 axis in
HFD-associated PCa growth but also suggests a novel mechanism of how
STAT3 is activated by PA. Our data suggest STAT3 as a therapeutic target
for the treatment of HFD-associated PCa.
UR - http://www.scopus.com/inward/record.url?scp=85071429750&partnerID=8YFLogxK
U2 - 10.1038/s41419-019-1842-4
DO - 10.1038/s41419-019-1842-4
M3 - Journal article
C2 - 31474764
AN - SCOPUS:85071429750
SN - 2041-4889
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 9
M1 - 637
ER -