TY - JOUR
T1 - Dasatinib Inhibits Lung Cancer Cell Growth and Patient Derived Tumor Growth in Mice by Targeting LIMK1
AU - Zhang, Man
AU - Tian, Jie
AU - Wang, Rui
AU - Song, Mengqiu
AU - Zhao, Ran
AU - Chen, Hanyong
AU - Liu, Kangdong
AU - Shim, Jung Hyun
AU - Zhu, Feng
AU - Dong, Zigang
AU - Lee, Mee Hyun
N1 - Publisher Copyright:
© Copyright © 2020 Zhang, Tian, Wang, Song, Zhao, Chen, Liu, Shim, Zhu, Dong and Lee.
PY - 2020/12/4
Y1 - 2020/12/4
N2 - Lung cancer is a leading cause cancer-related death with diversity. A promising approach to meet the need for improved cancer treatment is drug repurposing. Dasatinib, a second generation of tyrosine kinase inhibitors (TKIs), is a potent treatment agent for chronic myeloid leukemia (CML) approved by FDA, however, its off-targets and the underlying mechanisms in lung cancer have not been elucidated yet. LIM kinase 1 (LIMK1) is a serine/threonine kinase, which is highly upregulated in human cancers. Herein, we demonstrated that dasatinib dose-dependently blocked lung cancer cell proliferation and repressed LIMK1 activities by directly targeting LIMK1. It was confirmed that knockdown of LIMK1 expression suppressed lung cancer cell proliferation. From the in silico screening results, dasatinib may target to LIMK1. Indeed, dasatinib significantly inhibited the LIMK1 activity as evidenced by kinase and binding assay, and computational docking model analysis. Dasatinib inhibited lung cancer cell growth, while induced cell apoptosis as well as cell cycle arrest at the G1 phase. Meanwhile, dasatinib also suppressed the expression of markers relating cell cycle, cyclin D1, D3, and CDK2, and increased the levels of markers involved in cell apoptosis, cleaved caspase-3 and caspase-7 by downregulating phosphorylated LIMK1 (p-LIMK1) and cofilin (p-cofilin). Furthermore, in patient-derived xenografts (PDXs), dasatinib (30 mg/kg) significantly inhibited the growth of tumors in SCID mice which highly expressed LIMK1 without changing the bodyweight. In summary, our results indicate that dasatinib acts as a novel LIMK1 inhibitor to suppress the lung cancer cell proliferation in vitro and tumor growth in vivo, which suggests evidence for the application of dasatinib in lung cancer therapy.
AB - Lung cancer is a leading cause cancer-related death with diversity. A promising approach to meet the need for improved cancer treatment is drug repurposing. Dasatinib, a second generation of tyrosine kinase inhibitors (TKIs), is a potent treatment agent for chronic myeloid leukemia (CML) approved by FDA, however, its off-targets and the underlying mechanisms in lung cancer have not been elucidated yet. LIM kinase 1 (LIMK1) is a serine/threonine kinase, which is highly upregulated in human cancers. Herein, we demonstrated that dasatinib dose-dependently blocked lung cancer cell proliferation and repressed LIMK1 activities by directly targeting LIMK1. It was confirmed that knockdown of LIMK1 expression suppressed lung cancer cell proliferation. From the in silico screening results, dasatinib may target to LIMK1. Indeed, dasatinib significantly inhibited the LIMK1 activity as evidenced by kinase and binding assay, and computational docking model analysis. Dasatinib inhibited lung cancer cell growth, while induced cell apoptosis as well as cell cycle arrest at the G1 phase. Meanwhile, dasatinib also suppressed the expression of markers relating cell cycle, cyclin D1, D3, and CDK2, and increased the levels of markers involved in cell apoptosis, cleaved caspase-3 and caspase-7 by downregulating phosphorylated LIMK1 (p-LIMK1) and cofilin (p-cofilin). Furthermore, in patient-derived xenografts (PDXs), dasatinib (30 mg/kg) significantly inhibited the growth of tumors in SCID mice which highly expressed LIMK1 without changing the bodyweight. In summary, our results indicate that dasatinib acts as a novel LIMK1 inhibitor to suppress the lung cancer cell proliferation in vitro and tumor growth in vivo, which suggests evidence for the application of dasatinib in lung cancer therapy.
KW - LIMK1
KW - dasatinib
KW - non-small cell lung cancer
KW - off-targets
KW - patient-derived xenografts
UR - http://www.scopus.com/inward/record.url?scp=85097826591&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097826591&partnerID=8YFLogxK
U2 - 10.3389/fcell.2020.556532
DO - 10.3389/fcell.2020.556532
M3 - Article
C2 - 33344441
AN - SCOPUS:85097826591
SN - 2296-634X
VL - 8
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 556532
ER -