Development of a prolactin receptor-targeting fusion toxin using a prolactin antagonist and a recombinant form of Pseudomonas exotoxin A |
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Authors: | John?F.?Langenheim,Wen?Y.?Chen author-information" > author-information__contact u-icon-before" > mailto:wchen@ghs.org" title=" wchen@ghs.org" itemprop=" email" data-track=" click" data-track-action=" Email author" data-track-label=" " >Email author |
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Affiliation: | (1) Department of Biological Sciences, Clemson University, Clemson, SC, USA;(2) Oncology Research Institute, Greenville Hospital System, 900 West Faris Road, Greenville, SC 29605-4255, USA |
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Abstract: | Summary Human prolactin (hPRL) promotes the proliferation and differentiation of mammary epithelial cells during mammary gland development and has been linked to breast tumor development. The receptor for hPRL (hPRL-R) is elevated in a majority of human breast tumors, suggesting the overexpression of hPRL-R makes cancer cells highly sensitive to the mitogenic and anti-apoptotic activity of hPRL. These findings provide the rationale for the development of hPRL-R targeting breast cancer therapeutics. Previously, an hPRL-R antagonist, G129R, was developed that competitively binds to the hPRL-R resulting in growth inhibition and the induction of apoptosis in certain types of breast cancer cells. To further increase the potency of G129R, we fused G129R to a truncated form of Pseudomonas exotoxin A (PE40) that lacks the cell recognition domain of the toxin but retains the domains necessary for PE40_ to translocate into the cytosol and inhibit protein synthesis. We postulated that the fusion of G129R with PE40-KDEL would (1) deliver the recombinant toxin to breast cancer cells where hPRL-R is overexpressed; (2) block hPRL signaling via its G129R moiety; and (3) inhibit protein synthesis via its PE40-KDEL moiety. We demonstrate that the fusion toxin can competitively bind to hPRL-Rs on T-47D human breast cancer cells and inhibit STAT5 phosphorylation induced by hPRL. In addition, we show that G129R-PE40-KDEL is selectively cytotoxic to breast cancer cell lines expressing the hPRL-R and that cell death is associated with the inhibition of protein synthesis and does not involve caspase mediated apoptosis. |
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Keywords: | antagonist breast cancer exotoxin A fusion toxin G129R prolactin prolactin receptor |
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