title: Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways.
abstract: BACKGROUND
  Glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor of the central nervous system, is characterized by a relentless disease recurrence despite continued advancement in surgery, radiotherapy, and chemotherapy. Resistance to temozolomide (TMZ), a standard chemotherapeutic agent for GBM, remains a major challenge. Understanding the mechanisms behind TMZ resistance can direct the development of novel strategies for the prevention, monitoring, and treatment of tumor relapse.
  
  
  RESULTS
  Our research platform, based on the establishment of 2 pairs of TMZ-sensitive/resistant GBM cells (D54-S and D54-R; U87-S and U87-R), has successfully identified prolyl 4-hydroxylase, beta polypeptide (P4HB) over-expression to be associated with an increased IC50 of TMZ. Elevated P4HB expression was verified using in vivo xenografts developed from U87-R cells. Clinically, we found that P4HB was relatively up-regulated in the recurrent GBM specimens that were initially responsive to TMZ but later developed acquired resistance, when compared with treatment-naive tumors. Functionally, P4HB inhibition by RNAi knockdown and bacitracin inhibition could sensitize D54-R and U87-R cells to TMZ in vitro and in vivo, whereas over-expression of P4HB in vitro conferred resistance to TMZ in both D54-S and U87-S cells. Moreover, targeting P4HB blocked its protective function and sensitized glioma cells to TMZ through the PERK arm of the endoplasmic reticulum stress response.
  
  
  CONCLUSIONS
  Our study identified a novel target together with its functional pathway in the development of TMZ resistance. P4HB inhibition may be used alone or in combination with TMZ for the treatment of TMZ-resistant GBM.
authors: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, People’s Republic of China.
authors: Stella
authors: S
authors: Sun
authors: Derek
authors: D
authors: Lee
authors: Amy S W
authors: AS
authors: Ho
authors: Jenny K S
authors: JK
authors: Pu
authors: X Q
authors: XQ
authors: Zhang
authors: Nikki P
authors: NP
authors: Lee
authors: Philip J R
authors: PJ
authors: Day
authors: W M
authors: WM
authors: Lui
authors: C F
authors: CF
authors: Fung
authors: Gilberto K K
authors: GK
authors: Leung
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D003606:Dacarbazine; D011393:Procollagen-Proline Dioxygenase; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; C526497:P4HB protein, human; D019704:Protein Disulfide-Isomerases; D000077204:Temozolomide