Abstract | BACKGROUND: METHODS: In 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. RESULTS: 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. CONCLUSIONS: Collectively, these data are the first to show that iota toxin has the potential to be an effective, targeted therapy for breast cancer.
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Authors | Katerina D Fagan-Solis, Denise K Reaves, M Cristina Rangel, Michel R Popoff, Bradley G Stiles, Jodie M Fleming |
Journal | Molecular cancer
(Mol Cancer)
Vol. 13
Pg. 163
(Jul 02 2014)
ISSN: 1476-4598 [Electronic] England |
PMID | 24990559
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Bacterial Toxins
- CD44 protein, human
- Hyaluronan Receptors
- Lipoproteins
- Receptors, Lipoprotein
- iota toxin, Clostridium perfringens
- ADP Ribose Transferases
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Topics |
- ADP Ribose Transferases
(administration & dosage)
- Bacterial Toxins
(administration & dosage)
- Breast Neoplasms
(drug therapy, genetics, metabolism)
- Clostridium
(genetics)
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Hyaluronan Receptors
(genetics, metabolism)
- Lipolysis
(drug effects)
- Lipoproteins
(genetics, metabolism)
- MCF-7 Cells
- Receptors, Lipoprotein
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