Abstract
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.
Highlights
Gastric cancer is one of the most common causes of cancerrelated mortality worldwide [1]
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
PAK4 expression and activity are elevated in CDDP-resistant gastric cancer cells To explore the effect of PAK4 on CDDP resistance in gastric cancer cells, we first established two CDDP-resistant gastric cancer cell lines-AGS/CDDP and MKN-45/CDDP by continuous exposure to CDDP starting at 0.1 μg/ml and increasing in a stepwise manner to 1 μg/ml
Summary
Gastric cancer is one of the most common causes of cancerrelated mortality worldwide [1]. In a phase II study, the response rate of CDDP treatment against advanced gastric cancer was 22 % [2] and cases of complete remission were rare. Some CDDP-based combination chemotherapy have been used to improve the treatment outcomes and shown high response rates [3,4]. The small GTPases, i.e. Ras, Rho, Rac and Cdc contribute to many hallmarks of cancer. The PAKs (p21-activated kinases) are among the best characterized downstream effectors of Rac and Cdc. PAKs are overexpressed and/or hyperactivated in several human tumours such as breast cancer, colon cancer, lung cancer and gastric cancer [6,7].
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