p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells.
p21-activated kinase 5 (PAK5) is a recently identified member of the group B PAK family. The PAK proteins are effectors of the small GTPase Cdc42 and Rac1 and are known to regulate cell motility and activate cell-survival signaling pathways. Especially, the mitochondrial localization of PAK5 is vital to its effects on apoptosis and cell survival. Previously, we demonstrated that PAK5 expression increased significantly during the malignant progression of colorectal carcinoma (CRC) and that PAK5 promoted CRC metastasis by regulating CRC cell adhesion and migration. In the present study, we aim to investigate the role of PAK5 in camptothecin-induced apoptosis and its potential mechanism of action. Our results showed that overexpression of PAK5 inhibited camptothecin-induced apoptosis by inhibiting the activity of caspase-8 in CRC cells. Accordingly, knockdown of PAK5 in LoVo cells resulted in increased apoptosis. Mechanistically, we found that PAK5 directly phosphorylated Bad on serine 112 and indirectly led to phosphorylation of serine 136 via the Akt pathway. In conclusion, our study revealed previously unappreciated inhibitory role of PAK5 in camptothecin-induced apoptosis, thus suggesting PAK5 as a novel therapeutic target in CRC.
Wang
Xia
X
Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
Gong
Wei
W
Qing
Haitao
H
Geng
Yan
Y
Wang
Xinying
X
Zhang
Yongsheng
Y
Peng
Liang
L
Zhang
Hongquan
H
Jiang
Bo
B
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D010766:Phosphorylation; D010957:Plasmids; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D051025:bcl-Associated Death Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; C494819:BAD protein, human; D051025:bcl-Associated Death Protein; D011065:Poly(ADP-ribose) Polymerases; C443802:PAK5 protein, human; D054462:p21-Activated Kinases; D053181:Caspase 8; D002166:Camptothecin