PMID- 30959969
OWN - NLM
STAT- MEDLINE
DCOM- 20190719
LR  - 20211204
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 24
IP  - 7
DP  - 2019 Apr 7
TI  - Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but 
      Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling.
LID - 10.3390/molecules24071363 [doi]
LID - 1363
AB  - Ponatinib is a multi-target protein tyrosine kinase inhibitor, and its effects on 
      hepatocellular carcinoma cells have not been previously explored. In the present 
      study, we investigated its effects on hepatocellular carcinoma cell growth and 
      the underlying mechanisms. Toward SK-Hep-1 and SNU-423 cells, ponatinib induces 
      apoptosis by upregulation of cleaved caspase-3 and -7 and promotes cell cycle 
      arrest in the G1 phase by inhibiting CDK4/6/CyclinD1 complex and phosphorylation 
      of retinoblastoma protein. It inhibits the growth-stimulating mitogen-activated 
      protein (MAP) kinase pathway, the phosphorylation of Src on both negative and 
      positive regulation sites, and Jak2 and Stat3 phosphorylation. Surprisingly, it 
      also activates the PDK1, the protein kinase B (Akt), and the mechanistic target 
      of rapamycin (mTOR) signaling pathway. Blocking mTOR signaling strongly 
      sensitizes cells to inhibition by ponatinib and makes ponatinib a much more 
      potent inhibitor of hepatocellular carcinoma cell proliferation. These findings 
      demonstrate that ponatinib exerts both positive and negative effects on 
      hepatocellular cell proliferation, and eliminating its growth-stimulating effects 
      by drug combination or potentially by chemical medication can significantly 
      improve its efficacy as an anti-cancer drug.
FAU - Liu, Chang
AU  - Liu C
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, Shanxi, China. xiaophailch@163.com.
FAU - Mu, Xiuli
AU  - Mu X
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, Shanxi, China. mu13333499415@163.com.
FAU - Wang, Xuan
AU  - Wang X
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, Shanxi, China. airourouxuan@163.com.
FAU - Zhang, Chan
AU  - Zhang C
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, Shanxi, China. qlgcj1120@sina.com.
FAU - Zhang, Lina
AU  - Zhang L
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, Shanxi, China. 18335183328@163.com.
FAU - Yu, Baofeng
AU  - Yu B
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, Shanxi, China. shanxiyangcheng@126.com.
FAU - Sun, Gongqin
AU  - Sun G
AD  - Department of Biochemistry and Molecular Biology, Shanxi Medical University, 
      Taiyuan 030001, Shanxi, China. gsun@uri.edu.
AD  - Department of Cell and Molecular Biology, University of Rhode Island, Kingston, 
      RI 02881, USA. gsun@uri.edu.
LA  - eng
GR  - 0128532/Hundred Talent Program of Shanxi Province/
PT  - Journal Article
DEP - 20190407
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Imidazoles)
RN  - 0 (PDK1 protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridazines)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 4340891KFS (ponatinib)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Cell Cycle Checkpoints/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Drug Resistance, Neoplasm
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Liver Neoplasms/metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyridazines/*pharmacology
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC6480565
OTO - NOTNLM
OT  - PDK1/Akt/mTOR signaling
OT  - apoptosis
OT  - liver cancer cells
OT  - ponatinib
OT  - proliferation
COIS- The authors declare no conflict of interest.
EDAT- 2019/04/10 06:00
MHDA- 2019/07/20 06:00
PMCR- 2019/04/07
CRDT- 2019/04/10 06:00
PHST- 2019/02/26 00:00 [received]
PHST- 2019/03/30 00:00 [revised]
PHST- 2019/04/04 00:00 [accepted]
PHST- 2019/04/10 06:00 [entrez]
PHST- 2019/04/10 06:00 [pubmed]
PHST- 2019/07/20 06:00 [medline]
PHST- 2019/04/07 00:00 [pmc-release]
AID - molecules24071363 [pii]
AID - molecules-24-01363 [pii]
AID - 10.3390/molecules24071363 [doi]
PST - epublish
SO  - Molecules. 2019 Apr 7;24(7):1363. doi: 10.3390/molecules24071363.