File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways

TitleInhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways
Authors
Issue Date2013
PublisherDuke University Press. The Journal's web site is located at http://neuro-oncology.dukejournals.org
Citation
Neuro-oncology, 2013, v. 15 n. 5, p. 562-577 How to Cite?
AbstractBACKGROUND: 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. METHODS AND 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.
Persistent Identifierhttp://hdl.handle.net/10722/182034
ISSN
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSun, Sen_US
dc.contributor.authorLee, Den_US
dc.contributor.authorHo, SWAen_US
dc.contributor.authorPu, JKSen_US
dc.contributor.authorZhang, Xen_US
dc.contributor.authorLee, NPYen_US
dc.contributor.authorDay, PJRen_US
dc.contributor.authorLui, WMen_US
dc.contributor.authorFung, CFen_US
dc.contributor.authorLeung, GKKen_US
dc.date.accessioned2013-04-17T07:19:17Z-
dc.date.available2013-04-17T07:19:17Z-
dc.date.issued2013en_US
dc.identifier.citationNeuro-oncology, 2013, v. 15 n. 5, p. 562-577en_US
dc.identifier.issn1523-5866-
dc.identifier.urihttp://hdl.handle.net/10722/182034-
dc.description.abstractBACKGROUND: 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. METHODS AND 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.-
dc.languageengen_US
dc.publisherDuke University Press. The Journal's web site is located at http://neuro-oncology.dukejournals.org-
dc.relation.ispartofNeuro-oncologyen_US
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents, Alkylating/pharmacology-
dc.subject.meshApoptosis/drug effects-
dc.subject.meshBlotting, Western-
dc.subject.meshBrain Neoplasms/drug therapy-
dc.titleInhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathwaysen_US
dc.typeArticleen_US
dc.identifier.emailSun, S: ssun@hku.hken_US
dc.identifier.emailLee, D: leederek@hku.hken_US
dc.identifier.emailHo, SWA: hoswa@hku.hken_US
dc.identifier.emailLee, NPY: nikkilee@hku.hken_US
dc.identifier.emailLui, WM: mattlui@hku.hken_US
dc.identifier.emailFung, CF: cffung@hkucc.hku.hken_US
dc.identifier.emailLeung, GKK: gilberto@hkucc.hku.hken_US
dc.identifier.authorityLee, NPY=rp00263en_US
dc.identifier.authorityLeung, GKK=rp00522en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1093/neuonc/not005-
dc.identifier.pmid23444257-
dc.identifier.pmcidPMC3635523-
dc.identifier.hkuros213889en_US
dc.identifier.volume15-
dc.identifier.issue5-
dc.identifier.spage562-
dc.identifier.epage577-
dc.identifier.isiWOS:000318570300007-
dc.publisher.placeDurham, NC-
dc.description.otherNeuro-oncology, 2013, v. 15 n. 5, p. 562-577-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats