Oncotarget

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

Mu Yao, Chanlu Xie, Mei-Yee Kiang, Ying Teng, David Harman, Jessamy Tiffen, Qian Wang, Paul Sved, Shisan Bao, Paul Witting, Jeff Holst and Qihan Dong _

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Oncotarget. 2015; 6:34458-34474. https://doi.org/10.18632/oncotarget.5277

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Abstract

Mu Yao1,2, Chanlu Xie1,2,3, Mei-Yee Kiang1,2, Ying Teng1,2, David Harman4, Jessamy Tiffen5,6, Qian Wang5,6, Paul Sved7, Shisan Bao8, Paul Witting8, Jeff Holst5,6, Qihan Dong1,2,3

1Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia

2Central Clinical School and Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia

3School of Biomedical and Health Sciences, University of Western Sydney, Parramatta, NSW 2751, Australia

4Molecular Medicine Research Group, University of Western Sydney, Parramatta, NSW 2751, Australia

5Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW 2050, Australia

6Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia

7Department of Urology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia

8Department 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 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.


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