title: Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer.
abstract: Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Emma
authors.initials: E
authors.lastname: Ito
authors.forename: Shijun
authors.initials: S
authors.lastname: Yue
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Moriyama
authors.forename: Angela B
authors.initials: AB
authors.lastname: Hui
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Alajez
authors.forename: Nirmal
authors.initials: N
authors.lastname: Bhogal
authors.forename: Guohua
authors.initials: G
authors.lastname: Li
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Bernard
authors.initials: B
authors.lastname: Cummings
authors.forename: Rob
authors.initials: R
authors.lastname: Bristow
authors.forename: Jeff
authors.initials: J
authors.lastname: Wrana
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000528:radiation effects; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy*; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D034622:RNA Interference; D011838:Radiation-Sensitizing Agents / Q000378:metabolism* / Q000627:therapeutic use*; D014575:Uroporphyrinogen Decarboxylase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007527:Isoenzymes; D011838:Radiation-Sensitizing Agents; D007501:Iron; D014575:Uroporphyrinogen Decarboxylase