Cytosolic Phospholipase A2-α: A Potential Therapeutic Target for Prostate Cancer
| Autor: | Kieran F. Scott, Mu Yao, Michael H. Gelb, Fiona Maclean, Manish I. Patel, Marzieh Niknami, Qihan Dong, Sasa Lu, Jaskirat Singh, Caroline Kurek, Pamela J. Russell, John Boulas, Nicholas J. C. King |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Small interfering RNA Apoptosis Biology Article chemistry.chemical_compound Prostate cancer Cytosol Cyclin D1 Phospholipase A2 Cell Line Tumor Internal medicine medicine Humans Enzyme Inhibitors Phosphorylation Protein kinase B Cell Proliferation Cell growth Group IV Phospholipases A2 Prostatic Neoplasms medicine.disease Endocrinology Oncology chemistry Cell culture Cancer research biology.protein lipids (amino acids peptides and proteins) Growth inhibition Proto-Oncogene Proteins c-akt |
| Zdroj: | Clinical Cancer Research. 14:8070-8079 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Cytosolic phospholipase A2-α (cPLA2-α) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-α in prostate cancer cell lines and tissue and the effect of targeting cPLA2-α in vitro and in vivo. Experimental Design: The expression of cPLA2-α was determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-α activity were determined after inhibition with cPLA2-α small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-α inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-α was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens. Results: cPLA2-α is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1 results in significant reductions in prostate cancer cell numbers, as a result of reduced proliferation as well as increased apoptosis, and this was also associated with a reduction in cPLA2-α activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by ∼33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA2-α is increased when hormone refractory is reached. Conclusions: Expression and activation of cPLA2-α are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA2-α results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer. |
| Databáze: | OpenAIRE |
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