TY - JOUR
T1 - MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction between Pancreatic Cancer Cells and Stellate Cells
AU - Inoue, Koetsu
AU - Ohtsuka, Hideo
AU - Tachikawa, Masanori
AU - Motoi, Fuyuhiko
AU - Shijo, Masahiro
AU - Douchi, Daisuke
AU - Kawasaki, Shuhei
AU - Kawaguchi, Kei
AU - Masuda, Kunihiro
AU - Fukase, Koji
AU - Naito, Takeshi
AU - Katayose, Yu
AU - Egawa, Shinichi
AU - Unno, Michiaki
AU - Terasaki, Tetsuya
N1 - Publisher Copyright:
© Wolters Kluwer Health, Inc. All rights reserved.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Objectives Platelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs. Methods In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. Results In PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. Conclusions The PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.
AB - Objectives Platelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs. Methods In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. Results In PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. Conclusions The PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.
KW - MK2461
KW - molecular therapeutics
KW - pancreatic cancer
KW - pancreatic stellate cell
KW - proteomics
UR - http://www.scopus.com/inward/record.url?scp=85012865825&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85012865825&partnerID=8YFLogxK
U2 - 10.1097/MPA.0000000000000778
DO - 10.1097/MPA.0000000000000778
M3 - Article
C2 - 28196027
AN - SCOPUS:85012865825
VL - 46
SP - 557
EP - 566
JO - Pancreas
JF - Pancreas
SN - 0885-3177
IS - 4
ER -
