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Conference Paper: Targeting of Mortalin-Mutant p53 Interactions by Mortalin shRNA Leads to Selective Apoptotic Death of Human Hepatocellular Carcinoma
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TitleTargeting of Mortalin-Mutant p53 Interactions by Mortalin shRNA Leads to Selective Apoptotic Death of Human Hepatocellular Carcinoma
 
AuthorsLu, WJ
Lee, NPY
Poon, RTP
Kaul, SC
Wadhwa, R
Luk, JMC
 
Issue Date2010
 
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.immunotherapy-journal.com
 
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. 901-902 [How to Cite?]
DOI: http://dx.doi.org/10.1097/CJI.0b013e3181f1e08d
 
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.
 
ISSN1524-9557
2013 Impact Factor: 3.354
2013 SCImago Journal Rankings: 1.704
 
DOIhttp://dx.doi.org/10.1097/CJI.0b013e3181f1e08d
 
DC FieldValue
dc.contributor.authorLu, WJ
 
dc.contributor.authorLee, NPY
 
dc.contributor.authorPoon, RTP
 
dc.contributor.authorKaul, SC
 
dc.contributor.authorWadhwa, R
 
dc.contributor.authorLuk, JMC
 
dc.date.accessioned2011-08-26T14:36:40Z
 
dc.date.available2011-08-26T14:36:40Z
 
dc.date.issued2010
 
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.description.naturelink_to_OA_fulltext
 
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. 901-902 [How to Cite?]
DOI: http://dx.doi.org/10.1097/CJI.0b013e3181f1e08d
 
dc.identifier.doihttp://dx.doi.org/10.1097/CJI.0b013e3181f1e08d
 
dc.identifier.epage902
 
dc.identifier.hkuros190049
 
dc.identifier.issn1524-9557
2013 Impact Factor: 3.354
2013 SCImago Journal Rankings: 1.704
 
dc.identifier.issue8
 
dc.identifier.spage901
 
dc.identifier.urihttp://hdl.handle.net/10722/137902
 
dc.identifier.volume33
 
dc.languageeng
 
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.immunotherapy-journal.com
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Immunotherapy
 
dc.titleTargeting of Mortalin-Mutant p53 Interactions by Mortalin shRNA Leads to Selective Apoptotic Death of Human Hepatocellular Carcinoma
 
dc.typeConference_Paper
 
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<contributor.author>Lee, NPY</contributor.author>
<contributor.author>Poon, RTP</contributor.author>
<contributor.author>Kaul, SC</contributor.author>
<contributor.author>Wadhwa, R</contributor.author>
<contributor.author>Luk, JMC</contributor.author>
<date.accessioned>2011-08-26T14:36:40Z</date.accessioned>
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<description.abstract>Restoration 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.</description.abstract>
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