title: Targeting cytosolic phospholipase A2 α in colorectal cancer cells inhibits constitutively activated protein kinase B (AKT) and cell proliferation.
abstract: 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.
authors.affiliation: Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: He
authors.affiliation: Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia. School of Science and Health, The University of Western Sydney, Australia.
authors.forename: Chanlu
authors.initials: C
authors.lastname: Xie
authors.affiliation: Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Sheng
authors.initials: S
authors.lastname: Hua
authors.affiliation: 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.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of General Surgery, Nanhui Central Hospital. Shanghai, China.
authors.forename: Tingfeng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Mu
authors.initials: M
authors.lastname: Yao
authors.affiliation: Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Soma
authors.initials: S
authors.lastname: Vignarajan
authors.affiliation: Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia. School of Science and Health, The University of Western Sydney, Australia.
authors.forename: Leila
authors.initials: L
authors.lastname: Hejazi
authors.affiliation: 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.
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
authors.affiliation: Central Clinical School and Bosch Institute, The University of Sydney and Department of Endocrinology and Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia. School of Science and Health, The University of Western Sydney, Australia.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053492:Elafin / Q000235:genetics; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D054467:Phospholipases A2 / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014162:Transfection
chemical_list: D053492:Elafin; C506806:PI3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D054467:Phospholipases A2