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Article: An Akt/hypoxia-inducible factor-1α/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells

TitleAn Akt/hypoxia-inducible factor-1α/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells
Authors
Issue Date2009
PublisherAmerican Association for Cancer Research.
Citation
Clinical Cancer Research, 2009, v. 15 n. 10, p. 3462-3471 How to Cite?
AbstractPurpose: The goals of the present study were to investigate the mechanism of hypoxia-mediated chemoresistance in liver cancer cells and tumorigenic hepatic progenitor (oval) cells and to determine whether disrupting an Akt/hypoxia-inducible factor-1α (HIF-1α)/platelet-derived growth factor (PDGF)-BB autocrine loop can enhance chemotherapeutic efficacy in hypoxia. Experimental Design: Five hepatocellular carcinoma (HCC) cell lines and two hepatic progenitor cell lines were treated in vitro with cisplatin under both normoxic and hypoxic conditions. To generate ischemic hypoxia for tumor cells in vivo, hepatic artery ligation was applied to an orthotopic HCC model. Cisplatin and YC1, which is a HIF-1α inhibitor, were administered by portal vein and intratumoral injections, respectively. Results: Cell viability was higher under hypoxic than normoxic conditions. HIF-1α and Akt were up-regulated under hypoxic conditions, forming an autocrine signaling loop with PDGF-BB. Akt/HIF-1α/PDGF-BB signaling regulated Akt to confer cisplatin resistance to HCC cell lines in vitro. This autocrine signaling loop also contributed to chemoresistance in the tumorigenic hepatic progenitor cell line PIL2 under hypoxic conditions but not in the nontumorigenic cell line PIL4. In an orthotopic HCC model, combining blockade of HIF-1α activity with ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to suppression of tumor growth and prolongation of animal survival. Conclusion: Blockade of Akt/HIF-1α/PDGF-BB autocrine signaling could enhance the chemosensitivity of liver cancer cells and tumorigenic hepatic progenitor cells under hypoxic conditions and thus provide an effective therapeutic strategy for HCC. © 2009 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/83427
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID
Funding AgencyGrant Number
NSFC/RGC Joint Research Scheme of the Hong Kong Special Administrative RegionN_HKU717/06
Funding Information:

Grant support: NSFC/RGC Joint Research Scheme of the Hong Kong Special Administrative Region (N_HKU717/06).

References

 

DC FieldValueLanguage
dc.contributor.authorChi, KLen_HK
dc.contributor.authorZhen, FYen_HK
dc.contributor.authorHo, DWen_HK
dc.contributor.authorNg, MNen_HK
dc.contributor.authorYeoh, GCTen_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorSheung, TFen_HK
dc.date.accessioned2010-09-06T08:40:55Z-
dc.date.available2010-09-06T08:40:55Z-
dc.date.issued2009en_HK
dc.identifier.citationClinical Cancer Research, 2009, v. 15 n. 10, p. 3462-3471en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/83427-
dc.description.abstractPurpose: The goals of the present study were to investigate the mechanism of hypoxia-mediated chemoresistance in liver cancer cells and tumorigenic hepatic progenitor (oval) cells and to determine whether disrupting an Akt/hypoxia-inducible factor-1α (HIF-1α)/platelet-derived growth factor (PDGF)-BB autocrine loop can enhance chemotherapeutic efficacy in hypoxia. Experimental Design: Five hepatocellular carcinoma (HCC) cell lines and two hepatic progenitor cell lines were treated in vitro with cisplatin under both normoxic and hypoxic conditions. To generate ischemic hypoxia for tumor cells in vivo, hepatic artery ligation was applied to an orthotopic HCC model. Cisplatin and YC1, which is a HIF-1α inhibitor, were administered by portal vein and intratumoral injections, respectively. Results: Cell viability was higher under hypoxic than normoxic conditions. HIF-1α and Akt were up-regulated under hypoxic conditions, forming an autocrine signaling loop with PDGF-BB. Akt/HIF-1α/PDGF-BB signaling regulated Akt to confer cisplatin resistance to HCC cell lines in vitro. This autocrine signaling loop also contributed to chemoresistance in the tumorigenic hepatic progenitor cell line PIL2 under hypoxic conditions but not in the nontumorigenic cell line PIL4. In an orthotopic HCC model, combining blockade of HIF-1α activity with ischemic hypoxia significantly enhanced the efficacy of chemotherapy, leading to suppression of tumor growth and prolongation of animal survival. Conclusion: Blockade of Akt/HIF-1α/PDGF-BB autocrine signaling could enhance the chemosensitivity of liver cancer cells and tumorigenic hepatic progenitor cells under hypoxic conditions and thus provide an effective therapeutic strategy for HCC. © 2009 American Association for Cancer Research.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research.en_HK
dc.relation.ispartofClinical Cancer Researchen_HK
dc.subject.meshAntineoplastic Agents - pharmacology-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshHypoxia-Inducible Factor 1, alpha Subunit - genetics - metabolism-
dc.subject.meshOncogene Protein v-akt - genetics - metabolism-
dc.subject.meshPlatelet-Derived Growth Factor - genetics - metabolism-
dc.titleAn Akt/hypoxia-inducible factor-1α/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cellsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1078-0432&volume=15&issue=10&spage=3462&epage=3471&date=2009&atitle=An+Akt/hypoxia-inducible+factor-1alpha/platelet-derived+growth+factor-BB+autocrine+loop+mediates+hypoxia-induced+chemoresistance+in+liver+cancer+cells+and+tumorigenic+hepatic+progenitor+cellsen_HK
dc.identifier.emailPoon, RTP: poontp@hkucc.hku.hken_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-08-2127en_HK
dc.identifier.pmid19447872-
dc.identifier.scopuseid_2-s2.0-66149180568en_HK
dc.identifier.hkuros169637en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66149180568&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume15en_HK
dc.identifier.issue10en_HK
dc.identifier.spage3462en_HK
dc.identifier.epage3471en_HK
dc.identifier.isiWOS:000266282600025-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridChi, KL=15070609500en_HK
dc.identifier.scopusauthoridZhen, FY=26658831000en_HK
dc.identifier.scopusauthoridHo, DW=7402971906en_HK
dc.identifier.scopusauthoridNg, MN=23478329500en_HK
dc.identifier.scopusauthoridYeoh, GCT=7006022067en_HK
dc.identifier.scopusauthoridPoon, RTP=7103097223en_HK
dc.identifier.scopusauthoridSheung, TF=6506234707en_HK

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