title: Targeting of cytosolic phospholipase A2α impedes cell cycle re-entry of quiescent prostate cancer cells.
abstract: Cell cycle re-entry of quiescent cancer cells has been proposed to be involved in cancer progression and recurrence. Cytosolic phospholipase A2α (cPLA2α) is an enzyme that hydrolyzes membrane glycerophospholipids to release arachidonic acid and lysophospholipids that are implicated in cancer cell proliferation. The aim of this study was to determine the role of cPLA2α in cell cycle re-entry of quiescent prostate cancer cells. When PC-3 and LNCaP cells were rendered to a quiescent state, the active form of cPLA2α with a phosphorylation at Ser505 was lower compared to their proliferating state. Conversely, the phospho-cPLA2α levels were resurgent during the induction of cell cycle re-entry. Pharmacological inhibition of cPLA2α with Efipladib upon induction of cell cycle re-entry inhibited the re-entry process, as manifested by refrained DNA synthesis, persistent high proportion of cells in G0/G1 and low percentage of cells in S and G2/M phases, together with a stagnant recovery of Ki-67 expression. Simultaneously, Efipladib prohibited the emergence of Skp2 while maintained p27 at a high level in the nuclear compartment during cell cycle re-entry. Inhibition of cPLA2α also prevented an accumulation of cyclin D1/CDK4, cyclin E/CDK2, phospho-pRb, pre-replicative complex proteins CDC6, MCM7, ORC6 and DNA synthesis-related protein PCNA during induction of cell cycle re-entry. Moreover, a pre-treatment of the prostate cancer cells with Efipladib during induction of cell cycle re-entry subsequently compromised their tumorigenic capacity in vivo. Hence, cPLA2α plays an important role in cell cycle re-entry by quiescent prostate cancer cells.
authors.affiliation: Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Mu
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.|School of Biomedical and Health Sciences, University of Western Sydney, Parramatta, NSW 2751, Australia.
authors.forename: Chanlu
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Mei-Yee
authors.initials: MY
authors.lastname: Kiang
authors.affiliation: Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Molecular Medicine Research Group, University of Western Sydney, Parramatta, NSW 2751, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Harman
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW 2050, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Jessamy
authors.initials: J
authors.lastname: Tiffen
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW 2050, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Urology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Sved
authors.affiliation: Department of Pathology, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Shisan
authors.initials: S
authors.lastname: Bao
authors.affiliation: Department of Pathology, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Witting
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW 2050, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.affiliation: Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.|Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia.|School of Biomedical and Health Sciences, University of Western Sydney, Parramatta, NSW 2751, Australia.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D001565:Benzoates; D013449:Sulfonamides; D054513:Group IV Phospholipases A2; C516389:PLA2G4A protein, human; C531068:efipladib
keywords: Skp2; cell cycle re-entry; p27; phospholipase A2α; prostate cancer