Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer.
Challenging the roles of CD44 and lipolysis stimulated lipoprotein receptor in conveying Clostridium perfringens iota toxin cytotoxicity in breast cancer.
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DOI：
10.1186/1476-4598-13-163
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发表时间：
2014-07-02
期刊：
影响因子：
37.3
通讯作者：
Fleming JM
中科院分区：
文献类型：
--
作者：
Fagan-Solis KD;Reaves DK;Rangel MC;Popoff MR;Stiles BG;Fleming JM
鉴于细菌毒素作为化疗工具的潜力，细菌毒素的转化探索已经成为研究的前沿。对选定组织的研究表明，产气荚膜梭菌iota毒素与CD 44和脂解刺激的脂蛋白受体（LSR）细胞表面蛋白结合。我们最近证明LSR表达与雌激素受体阳性乳腺癌相关，LSR信号传导指导侵袭性肿瘤起始细胞行为。在此，我们确定了组织特异性乳腺癌模型中iota毒素细胞毒性的机制，最终目标是为使用iota毒素作为靶向乳腺癌治疗奠定基础。使用体外模型系统来确定iota毒素对乳腺癌内在亚型的细胞毒性作用。过表达和敲低技术的使用证实了LSR和CD 44在调节iota毒素内吞作用和诱导细胞死亡中的作用。最后，使用细胞毒性测定来证明iota毒素对一组经验证的他莫昔芬抗性乳腺癌细胞系的作用。对14株乳腺癌细胞系的处理显示LSR+/CD 44-细胞系高度敏感，LSR+/CD 44+细胞系轻微敏感，LSR-/CD 44+细胞系对iota细胞毒性具有抗性。LSR表达的减少导致毒素敏感性的显著降低;然而，CD 44的过表达传递毒素抗性。CD 44过表达与毒素刺激的溶酶体形成减少和iota毒素的胞质水平降低相关。这些发现表明，CD 44的表达通过抑制乳腺癌细胞中的内吞作用而驱动iota毒素抗性，这是先前未定义的CD 44的作用。此外，他莫昔芬耐药乳腺癌细胞表现出LSR的稳健表达，并且对iota诱导的细胞毒性高度敏感。总的来说，这些数据是第一个表明iota毒素有可能成为乳腺癌的有效靶向治疗。
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 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. 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. 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.
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DOI：
10.1083/jcb.131.6.1623
发表时间：
1995-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bennett KL;Modrell B;Greenfield B;Bartolazzi A;Stamenkovic I;Peach R;Jackson DG;Spring F;Aruffo A
通讯作者：
Aruffo A
影响因子：
2.9
作者：
MANN, CJ;KHALLOU, J;BIHAIN, BE
通讯作者：
BIHAIN, BE
影响因子：
3.4
作者：
Giatromanolaki, Alexandra;Sivridis, Efthimios;Koukourakis, Michael I.
通讯作者：
Koukourakis, Michael I.
激素受体状态，肿瘤特征和预后：乳腺癌患者的前瞻性队列。
DOI：
10.1186/bcr1639
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dunnwald LK;Rossing MA;Li CI
通讯作者：
Li CI
影响因子：
7.4
作者：
Allred, DC;Brown, P;Medina, D
通讯作者：
Medina, D