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Conference Paper: Targeting of Mortalin-Mutant p53 Interactions by Mortalin shRNA Leads to Selective Apoptotic Death of Human Hepatocellular Carcinoma

TitleTargeting of Mortalin-Mutant p53 Interactions by Mortalin shRNA Leads to Selective Apoptotic Death of Human Hepatocellular Carcinoma
Authors
Issue Date2010
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.immunotherapy-journal.com
Citation
The 25th Annual Scientific Meeting of theInternational Society for Biological Therapy of Cancer, Washington, D.C., USA, 2-4 October 2010, In Journal of Immunotherapy, 2010, v. 33 n. 8, p. 901-902 How to Cite?
AbstractRestoration of deregulated apoptotic pathway is one of the main strategies for cancer therapeutics. Mortalin/mitochondria heat shock protein 70 (mtHSP70) is a stress protein that is overexpressed in cancer cells and tissues, which has been proposed to have a role in human carcinogenesis. It was previously shown that mortalin interacts with wild type tumor suppressor protein p53 resulting in abrogation of its transcriptional activation and control of centrosome duplication functions, both tightly related to cancer development. Normal human fibroblasts were shown to lack mortalin-wild type p53 interactions. It was also identified as a marker for hepatocellular carcinoma (HCC) metastasis and recurrence by proteomics analysis of matched tumor and nontumor tissues. In this study, we examined mortalin expression in 100 HCC patients and found that its upregulation has strong correlation with tumor stage and microsatellite formation. In order to validate the critical role of mortalin in HCC development and progression, we recruited its shRNA in eight HCC-derived cell lines varying in p53 status (loss/mutant p53/wild type). MortalinshRNA caused apoptosis in most, but not all, HCC cell lines. By examination of mortalin-p53 interactions and molecular pathway for apoptosis, we found that induction of apoptosis by mortalinshRNA depended on occurrence of mortalin-mutant p53 interactions; the cell lines that lacked these interactions escaped apoptosis. Most importantly, mortalin-p53 interactions were induced by cellular stress by chemotherapeutic drug (cisplatin) following which the cells were sensitized to mortalin shRNA induced apoptosis. Based on the data, a model for mortalin and p53 interactions in cancer (physiologically a stressed condition) cells and use of mortalin-shRNA for selective killing of cancer cells is documented. Since p53 mutations are found in more than 80% of the tumors, mortalin shRNA is proposed as an effective cancer cell specific therapeutic tool.
Persistent Identifierhttp://hdl.handle.net/10722/137902
ISSN
2014 Impact Factor: 4.008
2014 SCImago Journal Rankings: 1.436

 

DC FieldValueLanguage
dc.contributor.authorLu, WJen_US
dc.contributor.authorLee, NPYen_US
dc.contributor.authorPoon, RTPen_US
dc.contributor.authorKaul, SCen_US
dc.contributor.authorWadhwa, Ren_US
dc.contributor.authorLuk, JMCen_US
dc.date.accessioned2011-08-26T14:36:40Z-
dc.date.available2011-08-26T14:36:40Z-
dc.date.issued2010en_US
dc.identifier.citationThe 25th Annual Scientific Meeting of theInternational Society for Biological Therapy of Cancer, Washington, D.C., USA, 2-4 October 2010, In Journal of Immunotherapy, 2010, v. 33 n. 8, p. 901-902en_US
dc.identifier.issn1524-9557-
dc.identifier.urihttp://hdl.handle.net/10722/137902-
dc.description.abstractRestoration of deregulated apoptotic pathway is one of the main strategies for cancer therapeutics. Mortalin/mitochondria heat shock protein 70 (mtHSP70) is a stress protein that is overexpressed in cancer cells and tissues, which has been proposed to have a role in human carcinogenesis. It was previously shown that mortalin interacts with wild type tumor suppressor protein p53 resulting in abrogation of its transcriptional activation and control of centrosome duplication functions, both tightly related to cancer development. Normal human fibroblasts were shown to lack mortalin-wild type p53 interactions. It was also identified as a marker for hepatocellular carcinoma (HCC) metastasis and recurrence by proteomics analysis of matched tumor and nontumor tissues. In this study, we examined mortalin expression in 100 HCC patients and found that its upregulation has strong correlation with tumor stage and microsatellite formation. In order to validate the critical role of mortalin in HCC development and progression, we recruited its shRNA in eight HCC-derived cell lines varying in p53 status (loss/mutant p53/wild type). MortalinshRNA caused apoptosis in most, but not all, HCC cell lines. By examination of mortalin-p53 interactions and molecular pathway for apoptosis, we found that induction of apoptosis by mortalinshRNA depended on occurrence of mortalin-mutant p53 interactions; the cell lines that lacked these interactions escaped apoptosis. Most importantly, mortalin-p53 interactions were induced by cellular stress by chemotherapeutic drug (cisplatin) following which the cells were sensitized to mortalin shRNA induced apoptosis. Based on the data, a model for mortalin and p53 interactions in cancer (physiologically a stressed condition) cells and use of mortalin-shRNA for selective killing of cancer cells is documented. Since p53 mutations are found in more than 80% of the tumors, mortalin shRNA is proposed as an effective cancer cell specific therapeutic tool.-
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.immunotherapy-journal.com-
dc.relation.ispartofJournal of Immunotherapyen_US
dc.titleTargeting of Mortalin-Mutant p53 Interactions by Mortalin shRNA Leads to Selective Apoptotic Death of Human Hepatocellular Carcinomaen_US
dc.typeConference_Paperen_US
dc.identifier.emailLee, NPY: nikkilee@hku.hken_US
dc.identifier.emailPoon, RTP: poontp@hku.hken_US
dc.identifier.emailLuk, JMC: jmluk@hkucc.hku.hken_US
dc.identifier.authorityLee, NPY=rp00263en_US
dc.identifier.authorityPoon, RTP=rp00446en_US
dc.identifier.authorityLuk, JMC=rp00349en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1097/CJI.0b013e3181f1e08d-
dc.identifier.hkuros190049en_US
dc.identifier.volume33-
dc.identifier.issue8-
dc.identifier.spage901-
dc.identifier.epage902-
dc.publisher.placeUnited States-

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