title: HSP90 inhibition downregulates thymidylate synthase and sensitizes colorectal cancer cell lines to the effect of 5FU-based chemotherapy.
abstract: Cell cycle progression and DNA synthesis are essential steps in cancer cell growth. Thymidylate synthase (TS) is a therapeutic target for 5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize colorectal cancer (CRC) cell lines to the effects of 5FU. Treatment with ganetespib (50 nM) for 24 hours inhibited cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29). This was associated with downregulation of E2F1 and its target gene TS. In addition, ganetespib inhibited PI3K/Akt and ERK signalling pathways. Similar effects were observed with HSP90 knockdown in both cell lines. Ganetespib sensitized CRC cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib, oxaliplatin and 5FU. In this study, we present in vitro and animal data supporting that the targeting of HSP90 decreases CRC cell survival and proliferation. Ganetespib sensitizes CRC cell lines to the effects of 5FU-based chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in CRC.
authors.affiliation: Department of Hematology and Medical Oncology, Atlanta, USA.
authors.forename: Ganji Purnachandra
authors.initials: GP
authors.lastname: Nagaraju
authors.affiliation: Department of Hematology and Medical Oncology, Atlanta, USA.
authors.forename: Olatunji B
authors.initials: OB
authors.lastname: Alese
authors.affiliation: Department of Radiation Oncology, Emory University, Atlanta, GA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Landry
authors.affiliation: Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Department of Hematology and Medical Oncology, Atlanta, USA.
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000077150:Oxaliplatin; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013940:Thymidylate Synthase / Q000378:metabolism*; D014162:Transfection; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; C533237:STA 9090; D014230:Triazoles; D000077150:Oxaliplatin; D013940:Thymidylate Synthase; D005472:Fluorouracil