title: PAK4 confers cisplatin resistance in gastric cancer cells via PI3K/Akt- and MEK/ERK-dependent pathways.
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.
authors.affiliation: Department of Gastroenterology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, People' Republic of China.
authors.forename: Xueqiong
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Gastroenterology, The Fifth Hospital of Wuhan, Wuhan 430050, People' Republic of China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Gastroenterology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, People' Republic of China.
authors.forename: Duan
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, People' Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Gastroenterology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, People' Republic of China.
authors.forename: Changshou
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, Longgang District Central Hospital of Shenzhen, Shenzhen 518116, People' Republic of China yangbing2005@126.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002867:Chromones; D002945:Cisplatin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011758:Pyrroles; D054462:p21-Activated Kinases; C550923:PF 3758309; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C116367:PAK4 protein, human
keywords: MEK/ERK; PI3K/Akt; cisplatin (CDDP); gastric cancer; p21-activated kinase 4 (PAK4)