Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer
Identifieur interne : 000094 ( Main/Exploration ); précédent : 000093; suivant : 000095Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer
Auteurs : Katerina D. Fagan-Solis [États-Unis] ; Denise K. Reaves [États-Unis] ; M Cristina Rangel [États-Unis] ; Michel R. Popoff [France] ; Bradley G. Stiles [États-Unis] ; Jodie M. Fleming [États-Unis]Source :
- Molecular Cancer [ 1476-4598 ] ; 2014.
Abstract
Translational exploration of bacterial toxins has come to the forefront of research given their potential as a chemotherapeutic tool. Studies in select tissues have demonstrated that
Treatment of 14 breast cancer cell lines revealed that LSR+/CD44- lines were highly sensitive, LSR+/CD44+ lines were slightly sensitive, and LSR-/CD44+ lines were resistant to iota cytotoxicity. Reduction in LSR expression resulted in a significant decrease in toxin sensitivity; however, overexpression of CD44 conveyed toxin resistance. CD44 overexpression was correlated with decreased toxin-stimulated lysosome formation and decreased cytosolic levels of iota toxin. These findings indicated that expression of CD44 drives iota toxin resistance through inhibition of endocytosis in breast cancer cells, a role not previously defined for CD44. Moreover, tamoxifen-resistant breast cancer cells exhibited robust expression of LSR and were highly sensitive to iota-induced cytotoxicity.
Collectively, these data are the first to show that iota toxin has the potential to be an effective, targeted therapy for breast cancer.
Url:
DOI: 10.1186/1476-4598-13-163
PubMed: 24990559
PubMed Central: 4086999
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying <italic>Clostridium perfringens</italic> iota toxin cytotoxicity in breast cancer</title><author><name sortKey="Fagan Solis, Katerina D" sort="Fagan Solis, Katerina D" uniqKey="Fagan Solis K" first="Katerina D" last="Fagan-Solis">Katerina D. Fagan-Solis</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Biology, North Carolina Central University, Durham, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, North Carolina Central University, Durham, NC</wicri:regionArea></affiliation></author><author><name sortKey="Reaves, Denise K" sort="Reaves, Denise K" uniqKey="Reaves D" first="Denise K" last="Reaves">Denise K. Reaves</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Biology, North Carolina Central University, Durham, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, North Carolina Central University, Durham, NC</wicri:regionArea></affiliation></author><author><name sortKey="Rangel, M Cristina" sort="Rangel, M Cristina" uniqKey="Rangel M" first="M Cristina" last="Rangel">M Cristina Rangel</name><affiliation wicri:level="1"><nlm:aff id="I2">Tumor Growth Factor Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, Frederick, MD, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Tumor Growth Factor Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, Frederick, MD</wicri:regionArea></affiliation></author><author><name sortKey="Popoff, Michel R" sort="Popoff, Michel R" uniqKey="Popoff M" first="Michel R" last="Popoff">Michel R. Popoff</name><affiliation wicri:level="1"><nlm:aff id="I3">Institut Pasteur, Anaerobic Bacteria and Toxins Unit, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Pasteur, Anaerobic Bacteria and Toxins Unit, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Stiles, Bradley G" sort="Stiles, Bradley G" uniqKey="Stiles B" first="Bradley G" last="Stiles">Bradley G. Stiles</name><affiliation wicri:level="1"><nlm:aff id="I4">Department of Biology, Wilson College, Chambersburg, PA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, Wilson College, Chambersburg, PA</wicri:regionArea></affiliation></author><author><name sortKey="Fleming, Jodie M" sort="Fleming, Jodie M" uniqKey="Fleming J" first="Jodie M" last="Fleming">Jodie M. Fleming</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Biology, North Carolina Central University, Durham, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, North Carolina Central University, Durham, NC</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24990559</idno><idno type="pmc">4086999</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086999</idno><idno type="RBID">PMC:4086999</idno><idno type="doi">10.1186/1476-4598-13-163</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000208</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000208</idno><idno type="wicri:Area/Pmc/Curation">000208</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000208</idno><idno type="wicri:Area/Pmc/Checkpoint">000067</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000067</idno><idno type="wicri:Area/Ncbi/Merge">000338</idno><idno type="wicri:Area/Ncbi/Curation">000338</idno><idno type="wicri:Area/Ncbi/Checkpoint">000338</idno><idno type="wicri:Area/Main/Merge">000094</idno><idno type="wicri:Area/Main/Curation">000094</idno><idno type="wicri:Area/Main/Exploration">000094</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying <italic>Clostridium perfringens</italic> iota toxin cytotoxicity in breast cancer</title><author><name sortKey="Fagan Solis, Katerina D" sort="Fagan Solis, Katerina D" uniqKey="Fagan Solis K" first="Katerina D" last="Fagan-Solis">Katerina D. Fagan-Solis</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Biology, North Carolina Central University, Durham, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, North Carolina Central University, Durham, NC</wicri:regionArea></affiliation></author><author><name sortKey="Reaves, Denise K" sort="Reaves, Denise K" uniqKey="Reaves D" first="Denise K" last="Reaves">Denise K. Reaves</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Biology, North Carolina Central University, Durham, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, North Carolina Central University, Durham, NC</wicri:regionArea></affiliation></author><author><name sortKey="Rangel, M Cristina" sort="Rangel, M Cristina" uniqKey="Rangel M" first="M Cristina" last="Rangel">M Cristina Rangel</name><affiliation wicri:level="1"><nlm:aff id="I2">Tumor Growth Factor Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, Frederick, MD, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Tumor Growth Factor Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, Frederick, MD</wicri:regionArea></affiliation></author><author><name sortKey="Popoff, Michel R" sort="Popoff, Michel R" uniqKey="Popoff M" first="Michel R" last="Popoff">Michel R. Popoff</name><affiliation wicri:level="1"><nlm:aff id="I3">Institut Pasteur, Anaerobic Bacteria and Toxins Unit, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Pasteur, Anaerobic Bacteria and Toxins Unit, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Stiles, Bradley G" sort="Stiles, Bradley G" uniqKey="Stiles B" first="Bradley G" last="Stiles">Bradley G. Stiles</name><affiliation wicri:level="1"><nlm:aff id="I4">Department of Biology, Wilson College, Chambersburg, PA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, Wilson College, Chambersburg, PA</wicri:regionArea></affiliation></author><author><name sortKey="Fleming, Jodie M" sort="Fleming, Jodie M" uniqKey="Fleming J" first="Jodie M" last="Fleming">Jodie M. Fleming</name><affiliation wicri:level="1"><nlm:aff id="I1">Department of Biology, North Carolina Central University, Durham, NC, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, North Carolina Central University, Durham, NC</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecular Cancer</title><idno type="eISSN">1476-4598</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Translational exploration of bacterial toxins has come to the forefront of research given their potential as a chemotherapeutic tool. Studies in select tissues have demonstrated that <italic>Clostridium perfringens</italic> iota toxin binds to CD44 and lipolysis stimulated lipoprotein receptor (LSR) cell-surface proteins. We recently demonstrated that LSR expression correlates with estrogen receptor positive breast cancers and that LSR signaling directs aggressive, tumor-initiating cell behaviors. Herein, we identify the mechanisms of iota toxin cytotoxicity in a tissue-specific, breast cancer model with the ultimate goal of laying the foundation for using iota toxin as a targeted breast cancer therapy.</p></sec><sec><title>Methods</title><p><italic>In vitro</italic> model systems were used to determine the cytotoxic effect of iota toxin on breast cancer intrinsic subtypes. The use of overexpression and knockdown technologies confirmed the roles of LSR and CD44 in regulating iota toxin endocytosis and induction of cell death. Lastly, cytotoxicity assays were used to demonstrate the effect of iota toxin on a validated set of tamoxifen resistant breast cancer cell lines.</p></sec><sec><title>Results</title><p>Treatment of 14 breast cancer cell lines revealed that LSR+/CD44- lines were highly sensitive, LSR+/CD44+ lines were slightly sensitive, and LSR-/CD44+ lines were resistant to iota cytotoxicity. Reduction in LSR expression resulted in a significant decrease in toxin sensitivity; however, overexpression of CD44 conveyed toxin resistance. CD44 overexpression was correlated with decreased toxin-stimulated lysosome formation and decreased cytosolic levels of iota toxin. These findings indicated that expression of CD44 drives iota toxin resistance through inhibition of endocytosis in breast cancer cells, a role not previously defined for CD44. Moreover, tamoxifen-resistant breast cancer cells exhibited robust expression of LSR and were highly sensitive to iota-induced cytotoxicity.</p></sec><sec><title>Conclusions</title><p>Collectively, these data are the first to show that iota toxin has the potential to be an effective, targeted therapy for breast cancer.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Carey, La" uniqKey="Carey L">LA Carey</name></author><author><name sortKey="Dees, Ec" uniqKey="Dees E">EC Dees</name></author><author><name sortKey="Sawyer, L" uniqKey="Sawyer L">L Sawyer</name></author><author><name sortKey="Gatti, L" uniqKey="Gatti L">L Gatti</name></author><author><name sortKey="Moore, Dt" uniqKey="Moore D">DT Moore</name></author><author><name sortKey="Collichio, F" uniqKey="Collichio F">F Collichio</name></author><author><name sortKey="Ollila, Dw" uniqKey="Ollila D">DW Ollila</name></author><author><name sortKey="Sartor, Ci" uniqKey="Sartor 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Kochi</name></author><author><name sortKey="Mock, M" uniqKey="Mock M">M Mock</name></author><author><name sortKey="Popoff, Mr" uniqKey="Popoff M">MR Popoff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fleming, Jm" uniqKey="Fleming J">JM Fleming</name></author><author><name sortKey="Ginsburg, E" uniqKey="Ginsburg E">E Ginsburg</name></author><author><name sortKey="Mcandrew, Cw" uniqKey="Mcandrew C">CW McAndrew</name></author><author><name sortKey="Heger, Cd" uniqKey="Heger C">CD Heger</name></author><author><name sortKey="Cheston, L" uniqKey="Cheston L">L Cheston</name></author><author><name sortKey="Rodriguez Canales, J" uniqKey="Rodriguez Canales J">J Rodriguez-Canales</name></author><author><name sortKey="Vonderhaar, Bk" uniqKey="Vonderhaar B">BK Vonderhaar</name></author><author><name sortKey="Goldsmith, P" uniqKey="Goldsmith P">P Goldsmith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pfaffl, Mw" uniqKey="Pfaffl M">MW Pfaffl</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>France</li><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Fagan Solis, Katerina D" sort="Fagan Solis, Katerina D" uniqKey="Fagan Solis K" first="Katerina D" last="Fagan-Solis">Katerina D. Fagan-Solis</name></noRegion><name sortKey="Fleming, Jodie M" sort="Fleming, Jodie M" uniqKey="Fleming J" first="Jodie M" last="Fleming">Jodie M. Fleming</name><name sortKey="Rangel, M Cristina" sort="Rangel, M Cristina" uniqKey="Rangel M" first="M Cristina" last="Rangel">M Cristina Rangel</name><name sortKey="Reaves, Denise K" sort="Reaves, Denise K" uniqKey="Reaves D" first="Denise K" last="Reaves">Denise K. Reaves</name><name sortKey="Stiles, Bradley G" sort="Stiles, Bradley G" uniqKey="Stiles B" first="Bradley G" last="Stiles">Bradley G. Stiles</name></country><country name="France"><noRegion><name sortKey="Popoff, Michel R" sort="Popoff, Michel R" uniqKey="Popoff M" first="Michel R" last="Popoff">Michel R. Popoff</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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