title: Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin PTTG1.
abstract: PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Castilla
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
authors.forename: M Luz
authors.initials: ML
authors.lastname: Flores
authors.affiliation: Department of Urology, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Medina
authors.affiliation: Department of Oncology, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Pérez-Valderrama
authors.affiliation: Department of Microbiology, Faculty of Biology, Universidad de Sevilla, Seville, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Romero
authors.affiliation: Department of Microbiology, Faculty of Biology, Universidad de Sevilla, Seville, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Tortolero
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain. Department of Pathology, Hospital Universitario Virgen del Rocío, Seville, Spain. csaez@cica.es mjapon@cica.es.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Japón
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain. Department of Pathology, Hospital Universitario Virgen del Rocío, Seville, Spain. csaez@cica.es mjapon@cica.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sáez
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D064249:Securin / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D034741:RNA, Small Interfering; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D017239:Paclitaxel