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01.12.2012 | Primary research | Ausgabe 1/2012 Open Access

Cancer Cell International 1/2012

Extracellular cyclophilin-A stimulates ERK1/2 phosphorylation in a cell-dependent manner but broadly stimulates nuclear factor kappa B

Cancer Cell International > Ausgabe 1/2012
Karim Bahmed, Curtis Henry, Michael Holliday, Jasmina Redzic, Madalina Ciobanu, Fengli Zhang, Colin Weekes, Robert Sclafani, James DeGregori, Elan Eisenmesser
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2867-12-19) contains supplementary material, which is available to authorized users.

Competing interests

There are no competing interests.

Authors’ contributions

KB designed and acquired all of the cell-based assays, MH and FZ produced and collected the nuclear magnetic resonance experiments. CH, JD, and RAS helped design and acquire the ERK1/2 phosphorylation experiments and provided expertise in culturing monocytic cell lines. JD and JR helped produce stable knockdown cell lines. MC and CW provided expertise in culturing pancreatic cancer cell lines. EZE helped design all of the experiments. All authors read and approved the final manuscript.



Although the peptidyl-prolyl isomerase, cyclophilin-A (peptidyl-prolyl isomerase, PPIA), has been studied for decades in the context of its intracellular functions, its extracellular roles as a major contributor to both inflammation and multiple cancers have more recently emerged. A wide range of activities have been ascribed to extracellular PPIA that include induction of cytokine and matrix metalloproteinase (MMP) secretion, which potentially underlie its roles in inflammation and tumorigenesis. However, there have been conflicting reports as to which particular signaling events are under extracellular PPIA regulation, which may be due to either cell-dependent responses and/or the use of commercial preparations recently shown to be highly impure.


We have produced and validated the purity of recombinant PPIA in order to subject it to a comparative analysis between different cell types. Specifically, we have used a combination of multiple methods such as luciferase reporter screens, translocation assays, phosphorylation assays, and nuclear magnetic resonance to compare extracellular PPIA activities in several different cell lines that included epithelial and monocytic cells.


Our findings have revealed that extracellular PPIA activity is cell type-dependent and that PPIA signals via multiple cellular receptors beyond the single transmembrane receptor previously identified, Extracellular Matrix MetalloPRoteinase Inducer (EMMPRIN). Finally, while our studies provide important insight into the cell-specific responses, they also indicate that there are consistent responses such as nuclear factor kappa B (NFκB) signaling induced in all cell lines tested.


We conclude that although extracellular PPIA activates several common pathways, it also targets different receptors in different cell types, resulting in a complex, integrated signaling network that is cell type-specific.
Additional file 2: Figure S2. The effect of extracellular PPIA on cellular proliferation. Cell cycle was monitored 24 h post incubation using FACS analysis with either buffer alone or recombinant PPIA in (A) HEK293T cells, (B) MOLM13 cells, (C) PANC-1 cells, and (D) L3.6pL cells. No apparent effect was observed. (JPEG 329 KB)
Additional file 4: Figure S4. Further characterization of PPIA-mediated activation of NFκB. A) An NFκB translocation assay was conducted as in Figure 3A, but using the PPIA active site point mutation, PPIA R55A. B) IκBα degradation is shown after treatment with recombinant PPIA. (JPEG 271 KB)
Additional file 5: Luciferase Reporter Plasmid Sources. (DOC 26 KB)
Authors’ original file for figure 1
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