Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer

Molecular Cancer

Research

Jodie M Fleming¹  Katerina D Fagan-Solis¹  Denise K Reaves¹  Bradley G Stiles²  Michel R Popoff³  M Cristina Rangel⁴ 

[1] Department of Biology, North Carolina Central University, Durham, NC, USA;Department of Biology, Wilson College, Chambersburg, PA, USA;Institut Pasteur, Anaerobic Bacteria and Toxins Unit, Paris, France;Tumor Growth Factor Section, Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, Frederick, MD, USA;

关键词: Clostridium perfringens;    Lipolysis stimulated lipoprotein receptor;    CD44;    Breast cancer;    Endocytosis;    Cytotoxicity;    Tamoxifen resistance;   

DOI  :  10.1186/1476-4598-13-163

 received in 2014-04-15, accepted in 2014-06-24,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundTranslational 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 Clostridium perfringens 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.MethodsIn vitro 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.ResultsTreatment 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.ConclusionsCollectively, these data are the first to show that iota toxin has the potential to be an effective, targeted therapy for breast cancer.

【 授权许可】

Unknown   
© Fagan-Solis et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.