title: PTTG1 attenuates drug-induced cellular senescence.
abstract: As PTTG1 (pituitary tumor transforming gene) abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1(-/-)) exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1(-/-) senescent cells increased ∼4 fold as compared to WT PTTG1-replete cells (p<0.001). p21, an important regulator of cell senescence, was induced ∼3 fold in HCT116 PTTG1(-/-) cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1(-/-) cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1(-/-) HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1(-/-) tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes.
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Yunguang
authors.initials: Y
authors.lastname: Tong
authors.forename: Weijiang
authors.initials: W
authors.lastname: Zhao
authors.forename: Cuiqi
authors.initials: C
authors.lastname: Zhou
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D064249:Securin; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D064249:Securin; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; C578002:pituitary tumor-transforming protein 1, human; C012589:trichostatin A; D004317:Doxorubicin