PMID- 33961012
OWN - NLM
STAT- MEDLINE
DCOM- 20210805
LR  - 20211204
IS  - 1745-7270 (Electronic)
IS  - 1672-9145 (Linking)
VI  - 53
IP  - 7
DP  - 2021 Jul 5
TI  - Dasatinib inhibits proliferation of liver cancer cells, but activation of 
      Akt/mTOR compromises dasatinib as a cancer drug.
PG  - 823-836
LID - 10.1093/abbs/gmab061 [doi]
AB  - Dasatinib is a multi-target protein tyrosine kinase inhibitor. Due to its potent 
      inhibition of Src, Abl, the platelet-derived growth factor receptor (PDGFR) 
      family kinases, and other oncogenic kinases, it has been investigated as a 
      targeted therapy for a broad spectrum of cancer types. However, its efficacy has 
      not been significantly extended beyond leukemia. The mechanism of resistance to 
      dasatinib in a wide array of cancers is not clear. In the present study, we 
      investigated the effect of dasatinib on hepatocellular carcinoma cell growth and 
      explored the underlying mechanisms. Our results showed that dasatinib potently 
      inhibited the proliferation of SNU-449 cells, but not that of other cell lines, 
      such as SK-Hep-1, even though it inhibited the phosphorylation of Src on both 
      negative and positive regulation sites in all these cells. Dasatinib activated 
      the phosphoinositide-dependent protein kinase1 (PDK1)/protein kinase B 
      (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in SK-Hep-1 cells, 
      but not in SNU-449 cells. Blocking the Akt/mTOR signaling pathway strongly 
      promoted the efficacy of dasatinib in SK-Hep-1 cells. In SNU-449 cells, dasatinib 
      promoted apoptosis and the cleavage of caspase-3 and caspase-7, induced cell 
      cycle arrest in the G1 phase, and inhibited the expression of Cyclin-dependent 
      kinase (CDK4)/6/CyclinD1 complex. These findings demonstrate that dasatinib 
      exerts its anti-proliferative effect on hepatocellular cell proliferation by 
      blocking the Src family kinases; however, it causes Akt activation, which 
      compromises dasatinib as an anti-cancer drug.
CI  - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the 
      Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All 
      rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
FAU - Liu, Chang
AU  - Liu C
AD  - Department of Biochemistry and Molecular Biology, Changzhi Medical College, 
      Changzhi 046000, China.
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Zhu, Xiaoxia
AU  - Zhu X
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Jia, Yuqi
AU  - Jia Y
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Chi, Fenqing
AU  - Chi F
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Qin, Keru
AU  - Qin K
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Pei, Jinhong
AU  - Pei J
AD  - Department of Biochemistry and Molecular Biology, Changzhi Medical College, 
      Changzhi 046000, China.
FAU - Zhang, Chan
AU  - Zhang C
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Mu, Xiuli
AU  - Mu X
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Zhang, Hongwei
AU  - Zhang H
AD  - Department of Hematology, Affiliated Tumor Hospital of Shanxi Medical University, 
      Taiyuan 030013, China.
FAU - Dong, Xiushan
AU  - Dong X
AD  - Department of General Surgery, Shanxi Bethune Hospital, Taiyuan 030032, China.
FAU - Xu, Jun
AU  - Xu J
AD  - Department of General Surgery, The First Hospital of Shanxi Medical University, 
      Taiyuan 030001, China.
FAU - Yu, Baofeng
AU  - Yu B
AUID- ORCID: 0000-0001-7865-5419
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, China.
LA  - eng
GR  - 30901821, 82072737/National Natural Science Foundation of China/
GR  - No. BS202007/Scientific Research Starting Foundation for Doctor of Changzhi 
      Medical College/
GR  - 1331KSC/Shanxi "1331 Project" Key Subjects Construction, China/
GR  - 201703D421023/Key R & D Projects in Shanxi Province, China/
GR  - KLMEC/SXMU-202111/Open Fund from Key Laboratory of Cellular Physiology (Shanxi 
      Medical University), Ministry of Education, China/
GR  - 201701D121165, 201901D111190/Nature science project of Shanxi Province, China/
GR  - 2020-194/Research Project Supported by Shanxi Scholarship Council of China/
PT  - Journal Article
PL  - China
TA  - Acta Biochim Biophys Sin (Shanghai)
JT  - Acta biochimica et biophysica Sinica
JID - 101206716
RN  - 0 (Antineoplastic Agents)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RBZ1571X5H (Dasatinib)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - *Carcinoma, Hepatocellular/drug therapy/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Dasatinib/*pharmacology
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - *Liver Neoplasms/drug therapy/genetics/metabolism/pathology
MH  - *Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Signal Transduction/*drug effects/genetics
MH  - *TOR Serine-Threonine Kinases/genetics/metabolism
OTO - NOTNLM
OT  - Akt-mTOR signaling
OT  - SK-Hep-1
OT  - SNU-449
OT  - dasatinib
EDAT- 2021/05/08 06:00
MHDA- 2021/08/06 06:00
CRDT- 2021/05/07 12:48
PHST- 2020/12/12 00:00 [received]
PHST- 2021/05/08 06:00 [pubmed]
PHST- 2021/08/06 06:00 [medline]
PHST- 2021/05/07 12:48 [entrez]
AID - 6271519 [pii]
AID - 10.1093/abbs/gmab061 [doi]
PST - ppublish
SO  - Acta Biochim Biophys Sin (Shanghai). 2021 Jul 5;53(7):823-836. doi: 
      10.1093/abbs/gmab061.