TY - JOUR
T1 - Targeting of cytosolic phospholipase A2α impedes cell cycle re-entry of quiescent prostate cancer cells
AU - Yao, Mu
AU - Xie, Chanlu
AU - Kiang, Mei-Yee
AU - Teng, Ying
AU - Harman, David
AU - Tiffen, Jessamy
AU - Wang, Qian
AU - Sved, Paul
AU - Bao, Shisan
AU - Witting, Paul
AU - Holst, Jeff
AU - Dong, Qihan
PY - 2015
Y1 - 2015
N2 - 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 phosphor-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, phosphor-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.
AB - 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 phosphor-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, phosphor-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.
KW - cancer
KW - cell cycle
KW - phospholipases
KW - prostate
UR - http://handle.uws.edu.au:8081/1959.7/uws:32015
U2 - 10.18632/oncotarget.5277
DO - 10.18632/oncotarget.5277
M3 - Article
SN - 1949-2553
VL - 6
SP - 34458
EP - 34474
JO - Oncotarget
JF - Oncotarget
IS - 33
ER -