Cytosolic phospholipase A2α sustains pAKT, pERK and AR levels in PTEN-null/mutated prostate cancer cells

Biochim Biophys Acta. 2013 Jun;1831(6):1146-57. doi: 10.1016/j.bbalip.2013.02.011. Epub 2013 Mar 14.

Abstract

Constitutive phosphorylation of protein kinase B (AKT) is a common feature of cancer caused by genetic alteration in the phosphatase and tensin homolog (PTEN) gene and is associated with poor prognosis. This study determined the role of cytosolic phospholipase A2α (cPLA2α) in AKT, extracellular signal-regulated kinase (ERK) and androgen receptor (AR) signaling in PTEN-null/mutated prostate cancer cells. Doxycycline (Dox)-induced expression of cPLA2α led to an increase in pAKT, pGSK3β and cyclin D1 levels in LNCaP cells that possess a PTEN frame-shift mutation. In contrast, silencing cPLA2α expression with siRNA decreased pAKT, pGSK3β and cyclin D1 levels in both PC-3 (PTEN deletion) and LNCaP cells. Silencing of cPLA2α decreased pERK and AR protein levels. The inhibitory effect of cPLA2α siRNA on pAKT and AR protein levels was reduced by the addition of arachidonic acid (AA), whereas the stimulatory effect of AA on pAKT, pERK and AR levels was decreased by an inhibitor of 5-hydroxyeicosatetraenoic acid production. Pharmacological blockade of cPLA2α with Efipladib reduced pAKT and AR levels with a concomitant inhibition of PC-3 and LNCaP cell proliferation. These results demonstrate an important role for cPLA2α in sustaining AKT, ERK and AR signaling in PTEN-null/mutated prostate cancer cells and provide a potential molecular target for treating prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Doxycycline / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fatty Acids / metabolism
  • Group IV Phospholipases A2 / antagonists & inhibitors
  • Group IV Phospholipases A2 / genetics
  • Group IV Phospholipases A2 / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Male
  • Mutation / genetics
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation / drug effects
  • Prostate-Specific Antigen / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured

Substances

  • AR protein, human
  • Anti-Bacterial Agents
  • Fatty Acids
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Group IV Phospholipases A2
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Prostate-Specific Antigen
  • Doxycycline