Research Papers:

Targeting cytosolic phospholipase A2 α in colorectal cancer cells inhibits constitutively activated protein kinase B (AKT) and cell proliferation

Zhong Zheng, Xiangyi He, Chanlu Xie, Sheng Hua, Jianfang Li, Tingfeng Wang, Mu Yao, Soma Vignarajan, Ying Teng, Leila Hejazi, Bingya Liu and Qihan Dong _

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Oncotarget. 2014; 5:12304-12316. https://doi.org/10.18632/oncotarget.2639

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Zhong Zheng1,*, Xiangyi He2,*, Chanlu Xie3,6, Sheng Hua3, Jianfang Li4, Tingfeng Wang5, Mu Yao3, Soma Vignarajan3, Ying Teng3, Leila Hejazi3,6, Bingya Liu4 and Qihan Dong3,6

1 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

2 Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

3 Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia

4 Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, and Gastroenterology, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, China

5 Department of General Surgery, Nanhui Central Hospital. Shanghai, China

6 School of Science and Health, The University of Western Sydney, Australia

* These authors contributed equally to this work


Qihan Dong, email:

Bingya Liu, email:

Keywords: Cytosolic phospholipase A2α, AKT, Colorectal cancer, Efipladib

Received: September 09, 2014 Accepted: October 28, 2014 Published: October 28, 2014


A constitutive activation of protein kinase B (AKT) in a hyper-phosphorylated status at Ser473 is one of the hallmarks of anti-EGFR therapy-resistant colorectal cancer (CRC). The aim of this study was to examine the role of cytosolic phospholipase A2α (cPLA2α) on AKT phosphorylation at Ser473 and cell proliferation in CRC cells with mutation in phosphoinositide 3-kinase (PI3K). AKT phosphorylation at Ser473 was resistant to EGF stimulation in CRC cell lines of DLD-1 (PIK3CAE545K mutation) and HT-29 (PIK3CAP499T mutation). Over-expression of cPLA2α by stable transfection increased basal and EGF-stimulated AKT phosphorylation and proliferation in DLD-1 cells. In contrast, silencing of cPLA2α with siRNA or inhibition with Efipladib decreased basal and EGF-stimulated AKT phosphorylation and proliferation in HT-29. Treating animals transplanted with DLD-1 with Efipladib (10 mg/kg, i.p. daily) over 14 days reduced xenograft growth by >90% with a concomitant decrease in AKT phosphorylation. In human CRC tissue, cPLA2α expression and phosphorylation were increased in 63% (77/120) compared with adjacent normal mucosa determined by immunohistochemistry. We conclude that cPLA2α is required for sustaining AKT phosphorylation at Ser473 and cell proliferation in CRC cells with PI3K mutation, and may serve as a potential therapeutic target for treatment of CRC resistant to anti-EGFR therapy.

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