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Article: Growth inhibition of human cancer cells by 5-aza-2'-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status.

TitleGrowth inhibition of human cancer cells by 5-aza-2'-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status.
Authors
Issue Date2009
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org
Citation
Molecular Cancer Therapeutics, 2009, v. 8 n. 4, p. 779-85 How to Cite?
AbstractThe cytotoxicity of 5-aza-2'-deoxycytidine (DAC) has been linked to demethylation of the INK4a/ARF tumor suppressor gene locus in various cell systems, but the causality of this association remains unproven. To test this assumption, we have examined the effects of DAC in two human cancer cell lines of differing INK4a/ARF promoter methylation status: MDA-MB-468 breast cancer cells in which INK4a/ARF is unmethylated and normally expressed, and DLD-1 colorectal cancer cells in which INK4a/ARF is methylated and repressed. In MDA-MB-468 cells, DAC induces cytotoxicity in the absence of any detectable increase of p14 or p16 expression, whereas small interfering RNA knockdown of p16/p14 expression fails to attenuate DAC cytotoxicity. In DLD-1 cells, DAC demethylates INK4a/ARF and restores both p16 and p14 expression at concentrations that fail to cause detectable growth inhibition or apoptosis; moreover, neither ARF nor INK4a transgene expression inhibits DLD-1 cell growth despite normalization of p14 and p16 expression. These data imply that neither of these cell lines depends on up-regulated expression of INK4a/ARF for DAC cytotoxicity. We propose that optimal anticancer use of this drug will await unambiguous identification of those DAC target genes primarily responsible for triggering growth inhibition, followed by clarification as to whether these upstream events are caused by hypomethylation or DNA damage.
Persistent Identifierhttp://hdl.handle.net/10722/59153
ISSN
2015 Impact Factor: 5.579
2015 SCImago Journal Rankings: 3.224
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorXiong, Jen_HK
dc.contributor.authorEpstein, Ren_HK
dc.date.accessioned2010-05-31T03:43:54Z-
dc.date.available2010-05-31T03:43:54Z-
dc.date.issued2009en_HK
dc.identifier.citationMolecular Cancer Therapeutics, 2009, v. 8 n. 4, p. 779-85en_HK
dc.identifier.issn1535-7163en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59153-
dc.description.abstractThe cytotoxicity of 5-aza-2'-deoxycytidine (DAC) has been linked to demethylation of the INK4a/ARF tumor suppressor gene locus in various cell systems, but the causality of this association remains unproven. To test this assumption, we have examined the effects of DAC in two human cancer cell lines of differing INK4a/ARF promoter methylation status: MDA-MB-468 breast cancer cells in which INK4a/ARF is unmethylated and normally expressed, and DLD-1 colorectal cancer cells in which INK4a/ARF is methylated and repressed. In MDA-MB-468 cells, DAC induces cytotoxicity in the absence of any detectable increase of p14 or p16 expression, whereas small interfering RNA knockdown of p16/p14 expression fails to attenuate DAC cytotoxicity. In DLD-1 cells, DAC demethylates INK4a/ARF and restores both p16 and p14 expression at concentrations that fail to cause detectable growth inhibition or apoptosis; moreover, neither ARF nor INK4a transgene expression inhibits DLD-1 cell growth despite normalization of p14 and p16 expression. These data imply that neither of these cell lines depends on up-regulated expression of INK4a/ARF for DAC cytotoxicity. We propose that optimal anticancer use of this drug will await unambiguous identification of those DAC target genes primarily responsible for triggering growth inhibition, followed by clarification as to whether these upstream events are caused by hypomethylation or DNA damage.-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.orgen_HK
dc.relation.ispartofMolecular Cancer Therapeuticsen_HK
dc.subject.meshAntimetabolites, Antineoplastic - pharmacology-
dc.subject.meshAzacitidine - analogs & derivatives/pharmacology-
dc.subject.meshBreast Neoplasms/genetics - pathology-
dc.subject.meshColorectal Neoplasms/genetics - pathology-
dc.subject.meshCyclin-Dependent Kinase Inhibitor p16 - genetics/metabolism-
dc.titleGrowth inhibition of human cancer cells by 5-aza-2'-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status.en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1535-7163&volume=8&issue=4&spage=779&epage=85&date=2009&atitle=Growth+inhibition+of+human+cancer+cells+by+5-aza-2%27-deoxycytidine+does+not+correlate+with+its+effects+on+INK4a/ARF+expression+or+initial+promoter+methylation+status.en_HK
dc.identifier.emailXiong, J: jbxiong@hkucc.hku.hken_HK
dc.identifier.emailEpstein, R: repstein@hku.hken_HK
dc.identifier.authorityEpstein, R=rp00501en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/1535-7163.MCT-08-0926-
dc.identifier.pmid19372550-
dc.identifier.scopuseid_2-s2.0-66449127105-
dc.identifier.hkuros162577en_HK
dc.identifier.isiWOS:000265204500008-

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