Targeting of cytosolic phospholipase A2α impedes cell cycle re-entry of quiescent prostate cancer cells

// Mu Yao 1, 2 , Chanlu Xie 1, 2, 3 , Mei-Yee Kiang 1, 2 , Ying Teng 1, 2 , David Harman 4 , Jessamy Tiffen 5, 6 , Qian Wang 5, 6 , Paul Sved 7 , Shisan Bao 8 , Paul Witting 8 , Jeff Holst 5, 6 , Qihan Dong 1, 2, 3 1 Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia 2 Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia 3 School of Biomedical and Health Sciences, University of Western Sydney, Parramatta, NSW 2751, Australia 4 Molecular Medicine Research Group, University of Western Sydney, Parramatta, NSW 2751, Australia 5 Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW 2050, Australia 6 Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia 7 Department of Urology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia 8 Department of Pathology, The University of Sydney, Sydney, NSW 2006, Australia Correspondence to: Qihan Dong, e-mail: q.dong@uws.edu.au Mu Yao, e-mail: mu.yao@sydney.edu.au Keywords: prostate cancer, phospholipase A2α, cell cycle re-entry, p27, Skp2 Received: May 15, 2015      Accepted: September 14, 2015      Published: September 24, 2015 ABSTRACT Cell cycle re-entry of quiescent cancer cells has been proposed to be involved in cancer progression and recurrence. Cytosolic phospholipase A 2 α (cPLA 2 α) 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 cPLA 2 α 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 cPLA 2 α with a phosphorylation at Ser 505 was lower compared to their proliferating state. Conversely, the phospho-cPLA 2 α levels were resurgent during the induction of cell cycle re-entry. Pharmacological inhibition of cPLA 2 α 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 G 0 /G 1 and low percentage of cells in S and G 2 /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 cPLA 2 α 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, cPLA 2 α plays an important role in cell cycle re-entry by quiescent prostate cancer cells.