TY - JOUR
T1 - Anaplastic lymphoma kinase inhibitor NVP-TAE684 suppresses the proliferation of human pancreatic adenocarcinoma cells
AU - Duong, Hong Quan
AU - Than, Van Thai
AU - Nguyen, Huyen Trang
AU - Nguyen, Phuong Thoa
AU - Thi, Huyen Trang Ha
AU - Bui, Thi Ngoc Ha
AU - Dang, Vu Phuong Linh
AU - Dinh, Thi Thanh
AU - You, Kyu Sic
AU - Dang, The Hung
AU - Seong, Yeon Sun
N1 - Publisher Copyright:
© 2021 Spandidos Publications. All rights reserved.
PY - 2021/2/18
Y1 - 2021/2/18
N2 - Anaplastic lymphoma kinase (ALK) is known to be an important therapeutic target in various types of cancer. NVP-TAE684, a well-known inhibitor of ALK, was revealed to exert antitumor effects in several different malignan- cies. However, the molecular mechanisms responsible for these antitumor effects in cancer cells, including pancreatic adenocarcinoma cells, remain unknown. In the present study, NVP-TAE684 was investigated for its antitumor effects towards pancreatic adenocarcinoma cells. MTT assay, western blot analysis, flow cytometry, caspase-3/7 activity assay and Trypan blue exclusion assay were used and it was revealed that NVP-TAE684 suppressed the proliferation of seven human pancreatic adenocarcinoma cell lines (AsPC-1, Panc-1, MIA PaCa-2, Capan-1, CFPAC-1, Colo-357 and BxPC-3), and significantly increased G2/M arrest and apoptotic cell death. Furthermore, NVP-TAE684 inhibited the phosphorylation of ALK at Y1604, as well as that of downstream mediators such as AKT (S473) and ERK1/2 (Y202/T204). Notably, knocking down ALK with siRNAs also decreased prolifera- tion and promoted G2/M arrest and apoptosis. Furthermore, inhibition of ALK with NVP-TAE684 or siRNA synergisti- cally enhanced gemcitabine-induced cell death by inducing apoptosis. In conclusion, the findings of the present study indicated that NVP-TAE684 exerted its antitumor effects by inducing G2/M arrest and apoptosis via the inhibition of the ALK signaling pathway, and suggests its potential use as an antitumor agent against pancreatic adenocarcinoma.
AB - Anaplastic lymphoma kinase (ALK) is known to be an important therapeutic target in various types of cancer. NVP-TAE684, a well-known inhibitor of ALK, was revealed to exert antitumor effects in several different malignan- cies. However, the molecular mechanisms responsible for these antitumor effects in cancer cells, including pancreatic adenocarcinoma cells, remain unknown. In the present study, NVP-TAE684 was investigated for its antitumor effects towards pancreatic adenocarcinoma cells. MTT assay, western blot analysis, flow cytometry, caspase-3/7 activity assay and Trypan blue exclusion assay were used and it was revealed that NVP-TAE684 suppressed the proliferation of seven human pancreatic adenocarcinoma cell lines (AsPC-1, Panc-1, MIA PaCa-2, Capan-1, CFPAC-1, Colo-357 and BxPC-3), and significantly increased G2/M arrest and apoptotic cell death. Furthermore, NVP-TAE684 inhibited the phosphorylation of ALK at Y1604, as well as that of downstream mediators such as AKT (S473) and ERK1/2 (Y202/T204). Notably, knocking down ALK with siRNAs also decreased prolifera- tion and promoted G2/M arrest and apoptosis. Furthermore, inhibition of ALK with NVP-TAE684 or siRNA synergisti- cally enhanced gemcitabine-induced cell death by inducing apoptosis. In conclusion, the findings of the present study indicated that NVP-TAE684 exerted its antitumor effects by inducing G2/M arrest and apoptosis via the inhibition of the ALK signaling pathway, and suggests its potential use as an antitumor agent against pancreatic adenocarcinoma.
KW - Anaplastic lymphoma kinase inhibitor
KW - Apoptotic cell death
KW - Cell cycle arrest
KW - NVP-TAE684
KW - Pancreatic adenocarcinoma cells
UR - http://www.scopus.com/inward/record.url?scp=85101749782&partnerID=8YFLogxK
U2 - 10.3892/or.2021.7979
DO - 10.3892/or.2021.7979
M3 - Article
C2 - 33649854
AN - SCOPUS:85101749782
SN - 1021-335X
VL - 45
JO - Oncology Reports
JF - Oncology Reports
IS - 4
M1 - 28
ER -