EF24 induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by increasing PTEN expression.
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.
Selvendiran
Karuppaiyah
K
Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
Tong
Liyue
L
Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
Vishwanath
Shilpa
S
Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
Bratasz
Anna
A
Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
Trigg
Nancy J
NJ
Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
Kutala
Vijay K
VK
Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210.
Hideg
Kalman
K
Institute of Organic and Medicinal Chemistry, University of Pécs, H-7643 Pecs, Hungary.
Kuppusamy
Periannan
P
Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210. Electronic address: kuppusamy.1@osu.edu.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001597:Benzylidene Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival; D002945:Cisplatin; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D053222:Fas Ligand Protein / Q000096:biosynthesis; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D010881:Piperidones / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C524042:3,5-bis(2-fluorobenzylidene)piperidin-4-one; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D010881:Piperidones; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020169:Caspases; D002945:Cisplatin