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; Qihan Dong

doi:10.18632/oncotarget.5277

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

Oncotarget. 2015 Oct 27;6(33):34458-74. doi: 10.18632/oncotarget.5277.

Authors

Mu Yao^{1

2}, Chanlu Xie^{1

2

3}, Mei-Yee Kiang^{1

2}, Ying Teng^{1

2}, David Harman⁴, Jessamy Tiffen^{5

6}, Qian Wang^{5

6}, Paul Sved⁷, Shisan Bao⁸, Paul Witting⁸, Jeff Holst^{5

6}, Qihan Dong^{1

2

3}

Affiliations

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.

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.

Keywords: Skp2; cell cycle re-entry; p27; phospholipase A2α; prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzoates / pharmacology
Cell Cycle / drug effects
Cell Cycle / physiology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / physiology*
Flow Cytometry
Fluorescent Antibody Technique
Group IV Phospholipases A2 / metabolism*
Heterografts
Humans
Immunoblotting
Immunohistochemistry
Male
Mice
Mice, Nude
Prostatic Neoplasms / enzymology
Prostatic Neoplasms / pathology*
Sulfonamides / pharmacology

Substances

Benzoates
Sulfonamides
Group IV Phospholipases A2
PLA2G4A protein, human
efipladib