Abstract
We report that EF24, a synthetic compound 3,5-bis(2-flurobenzylidene)piperidin-4-one, greatly inhibits cisplatin-resistant (CR) human ovarian cancer cell proliferation. The inhibitory effect of EF24 on cell proliferation is associated with G(2)/M phase cell cycle arrest and increased G(2)/M checkpoint protein (pp53, p53, and p21) levels. Within 24 h following treatment, EF24 induced apoptosis in CR cells. The apoptosis was partially blocked by the general caspase inhibitor z-VAD. Within 12 h, EF24 induced a membranous FasL expression, consistent with a substantial decrease in the Ser(473) and Thr(308) phosphorylation of Akt, a known negative regulator of FasL transcription. Also, EF24 activated the phosphorylated PTEN and marginally up-regulated total PTEN expression through the inhibition of ubiquitin-mediated PTEN degradation. Suppression of PTEN expression with siRNA significantly reduced the p53 and p21 levels and activated Akt phosphorylation at Ser(473) and Thr(308), resulting in decreased apoptosis and increased cell survival. On the other hand, overexpression of PTEN markedly induced apoptosis. Our results clearly suggested that EF24 induced significant increase in PTEN expression. The up-regulation of PTEN inhibited Akt and MDM2, which enhanced the level of p53, thereby inducing G(2)/M arrest and apoptosis. Therefore, EF24 appears to have a potential therapeutic role in human ovarian cancer through the activation of PTEN.
Highlights
Drug resistance remains a major challenge in clinical cancer treatment [1]
In our efforts to study the efficacy and mechanisms of novel anticancer agents for ovarian carcinoma, we recently reported that curcumin, a major active component of Curcuma longa, induced cell cycle arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt/p38 pathways [22]
We observed a similar effect of EF24 on cisplatin-sensitive (CS) human ovarian cancer cells (Fig. 1C)
Summary
Drug resistance remains a major challenge in clinical cancer treatment [1]. Patients suffering from advanced ovarian carcinoma are, in most cases, initially responsive to chemotherapy; they later experience a relapse of the disease because of the eventual recurrence of the tumor and emergence of drugresistant tumor cells. Suppression of PTEN expression with siRNA significantly reduced the p53 and p21 levels and activated Akt phosphorylation at Ser473 and Thr308, resulting in decreased apoptosis and increased cell survival.
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