PAK4 confers cisplatin resistance in gastric cancer cells via PI3K/Akt- and MEK/ERK-dependent pathways

Autor: Jiarui Feng, Yu Ding, Duan Zeng, Xueqiong Fu, Changshou Yu, Bing Yang
Jazyk: angličtina
Rok vydání: 2014
Předmět:
MAPK/ERK pathway
lcsh:Life
lcsh:QR1-502
Biochemistry
PAK
p21-activated kinase
lcsh:Microbiology
chemistry.chemical_compound
Mice
Phosphatidylinositol 3-Kinases
LY294002
Phosphoinositide-3 Kinase Inhibitors
cisplatin (CDDP)
Kinase
CDDP
cisplatin
HRP
horseradish peroxidase
Combination chemotherapy
female genital diseases and pregnancy complications
PI3K
phosphoinositide 3-kinase
MEK
MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase
inorganic chemicals
S1
MAP Kinase Signaling System
Morpholines
Biophysics
Mice
Nude
Biology
ERK
extracellular-signal-regulated kinase
S2
Stomach Neoplasms
Cell Line
Tumor
Animals
Humans
Pyrroles
p21-activated kinase 4 (PAK4)
Molecular Biology
Protein kinase B
neoplasms
PI3K/AKT/mTOR pathway
Akt
protein kinase B or PKB
Original Paper
PI3K/Akt
Akt/PKB signaling pathway
gastric cancer
Cell Biology
Xenograft Model Antitumor Assays
lcsh:QH501-531
chemistry
p21-Activated Kinases
siRNA
small interfering RNA
Chromones
Drug Resistance
Neoplasm
Cancer cell
Cancer research
PAK4
p21-activated kinase 4
Pyrazoles
Cisplatin
Proto-Oncogene Proteins c-akt
MEK/ERK
Zdroj: Bioscience Reports, Vol 34, Iss 2, p e00094 (2014)
Bioscience Reports
ISSN: 1573-4935
Popis: CDDP [cisplatin or cis-diamminedichloroplatinum(II)] and CDDP-based combination chemotherapy have been confirmed effective against gastric cancer. However, CDDP efficiency is limited because of development of drug resistance. In this study, we found that PAK4 (p21-activated kinase 4) expression and activity were elevated in gastric cancer cells with acquired CDDP resistance (AGS/CDDP and MKN-45/CDDP) compared with their parental cells. Inhibition of PAK4 or knockdown of PAK4 expression by specific siRNA (small interfering RNA)-sensitized CDDP-resistant cells to CDDP and overcome CDDP resistance. Combination treatment of LY294002 [the inhibitor of PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B or PKB) pathway] or PD98509 {the inhibitor of MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] pathway} with PF-3758309 (the PAK4 inhibitor) resulted in increased CDDP efficacy compared with LY294002 or PD98509 alone. However, after the concomitant treatment of LY294002 and PD98509, PF-3758309 administration exerted no additional enhancement of CDDP cytotoxicity in CDDP-resistant cells. Inhibition of PAK4 by PF-3758309 could significantly suppress MEK/ERK and PI3K/Akt signalling in CDDP-resistant cells. Furthermore, inhibition of PI3K/Akt pathway while not MEK/ERK pathway could inhibit PAK4 activity in these cells. The in vivo results were similar with those of in vitro. In conclusion, these results indicate that PAK4 confers CDDP resistance via the activation of MEK/ERK and PI3K/Akt pathways. PAK4 and PI3K/Akt pathways can reciprocally activate each other. Therefore, PAK4 may be a potential target for overcoming CDDP resistance in gastric cancer.
Databáze: OpenAIRE
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