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

    Research output: Contribution to journalArticlepeer-review

    16 Citations (Scopus)

    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 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.
    Original languageEnglish
    Pages (from-to)34458-34474
    Number of pages17
    JournalOncotarget
    Volume6
    Issue number33
    DOIs
    Publication statusPublished - 2015

    Keywords

    • cancer
    • cell cycle
    • phospholipases
    • prostate

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