Function and modulation of Pdcd4 in ovarian cancer

Abstract

Programmed cell death 4 (Pdcd4), a novel gene and originally identified as the neoplastic transformation inhibitor, is attenuated in various cancer types. It has been shown to have tumor suppressor properties such as inhibiting cell proliferation and inducing apoptosis. Our previous study demonstrated a continuous down-regulation of Pdcd4 expression in the sequence of normal-borderline-malignant ovarian tissue samples, and a significant correlation of Pdcd4 expression with disease-free survival. The objective of the current study is to further investigate the function and modulation of Pdcd4 in ovarian cancer cells. Our in vitro studies demonstrated that ectopic Pdcd4 expression significantly inhibited ovarian cancer cell proliferation by up-regulation of cyclin dependent kinase inhibitors of p27 and p21 and subsequently leading to cell cycle arrest at G1 stage. Unlike other cancers, Pdcd4 neither induce ovarian cancer cell apoptosis, nor promote the cellular sensitivity in response to cisplatin treatment. Pdcd4 over-expressing ovarian cancer cells exhibited elevated phosphatase and tensin homolog (PTEN) and decreased p-Akt expressions. In addition, Pdcd4 expression was up-regulated and translocated from cell nucleus to cytoplasm upon serum withdrawal treatment, but was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of Pdcd4. In conclusion, loss of Pdcd4 may result in diminished cell ability to arrest at key checkpoint, leading to tumor development. The PI3K-Akt pathway may be involved in the regulation of Pdcd4 degradation in ovarian cancer cells. In response to the stress condition, Pdcd4 expression was altered and it was translocated to cytoplasm, suggesting that Pdcd4 was able to shuttle between cell compartments to perform its diverted functions.