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- Publisher Website: 10.1158/1078-0432.CCR-08-2127
- Scopus: eid_2-s2.0-66149180568
- PMID: 19447872
- WOS: WOS:000266282600025
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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
Title | 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 | ||||
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Authors | |||||
Issue Date | 2009 | ||||
Publisher | American Association for Cancer Research. | ||||
Citation | Clinical Cancer Research, 2009, v. 15 n. 10, p. 3462-3471 How to Cite? | ||||
Abstract | Purpose: 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 Identifier | http://hdl.handle.net/10722/83427 | ||||
ISSN | 2023 Impact Factor: 10.0 2023 SCImago Journal Rankings: 4.623 | ||||
ISI Accession Number ID |
Funding Information: Grant support: NSFC/RGC Joint Research Scheme of the Hong Kong Special Administrative Region (N_HKU717/06). | ||||
References |
DC Field | Value | Language |
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dc.contributor.author | Chi, KL | en_HK |
dc.contributor.author | Zhen, FY | en_HK |
dc.contributor.author | Ho, DW | en_HK |
dc.contributor.author | Ng, MN | en_HK |
dc.contributor.author | Yeoh, GCT | en_HK |
dc.contributor.author | Poon, RTP | en_HK |
dc.contributor.author | Sheung, TF | en_HK |
dc.date.accessioned | 2010-09-06T08:40:55Z | - |
dc.date.available | 2010-09-06T08:40:55Z | - |
dc.date.issued | 2009 | en_HK |
dc.identifier.citation | Clinical Cancer Research, 2009, v. 15 n. 10, p. 3462-3471 | en_HK |
dc.identifier.issn | 1078-0432 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/83427 | - |
dc.description.abstract | Purpose: 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.language | eng | en_HK |
dc.publisher | American Association for Cancer Research. | en_HK |
dc.relation.ispartof | Clinical Cancer Research | en_HK |
dc.subject.mesh | Antineoplastic Agents - pharmacology | - |
dc.subject.mesh | Drug Resistance, Neoplasm | - |
dc.subject.mesh | Hypoxia-Inducible Factor 1, alpha Subunit - genetics - metabolism | - |
dc.subject.mesh | Oncogene Protein v-akt - genetics - metabolism | - |
dc.subject.mesh | Platelet-Derived Growth Factor - genetics - metabolism | - |
dc.title | 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 | en_HK |
dc.type | Article | en_HK |
dc.identifier.openurl | http://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+cells | en_HK |
dc.identifier.email | Poon, RTP: poontp@hkucc.hku.hk | en_HK |
dc.identifier.authority | Poon, RTP=rp00446 | en_HK |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-08-2127 | en_HK |
dc.identifier.pmid | 19447872 | - |
dc.identifier.scopus | eid_2-s2.0-66149180568 | en_HK |
dc.identifier.hkuros | 169637 | en_HK |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-66149180568&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 15 | en_HK |
dc.identifier.issue | 10 | en_HK |
dc.identifier.spage | 3462 | en_HK |
dc.identifier.epage | 3471 | en_HK |
dc.identifier.isi | WOS:000266282600025 | - |
dc.publisher.place | United States | en_HK |
dc.identifier.scopusauthorid | Chi, KL=15070609500 | en_HK |
dc.identifier.scopusauthorid | Zhen, FY=26658831000 | en_HK |
dc.identifier.scopusauthorid | Ho, DW=7402971906 | en_HK |
dc.identifier.scopusauthorid | Ng, MN=23478329500 | en_HK |
dc.identifier.scopusauthorid | Yeoh, GCT=7006022067 | en_HK |
dc.identifier.scopusauthorid | Poon, RTP=7103097223 | en_HK |
dc.identifier.scopusauthorid | Sheung, TF=6506234707 | en_HK |
dc.identifier.issnl | 1078-0432 | - |