Secreted cyclophilin A mediates G1/S phase transition of cholangiocarcinoma cells via CD147/ERK1/2 pathway

Abstract

Cyclophilin A (CypA) was shown to be upregulated in human cholangiocarcinoma (CCA) tissues. Suppression of intracellular CypA (inCypA) significantly reduces cell proliferation in vitro and tumor growth in nude mice. In the present study, the effect and potential mechanism of secreted CypA (sCypA) on cell proliferation of CCA cell lines were further investigated. CCA cells were treated with sCypA-containing conditioned media (CM) or with purified recombinant human CypA (rhCypA). Cell proliferation, cell cycle, ERK1/2, p38 MAPK, NF-κB, and STAT3 activities were examined by MTS assay, flow cytometry, and Western blot. sCypA was detected in CM from MMNK1 (an immortalized human cholangiocyte cell line) and six CCA cell lines. The sCypA levels corresponded to the inCypA levels indicating the intracellular origin of sCypA. Both sCypA-containing CM and rhCypA significantly increased proliferation of CCA cells. CD147 depletion by shRNA-knockdown or neutralizing with a CD147-monoclonal antibody significantly reduced sCypA-, and rhCypA-mediated cell proliferation. Upon rhCypA treatment, ERK1/2 was rapidly phosphorylated; whereas neutralizing CD147 inhibited ERK1/2 phosphorylation. Cell cycle analysis showed a significant increase in S phase and decrease in G1 population in rhCypA-treated cells. The expression levels of cyclin D1 and phosphorylated-retinoblastoma protein in the rhCypA-treated cells were increased compared with those in the non-treated control cells. p38 MAPK pathway was shown to be suppressed in siCypA-treated cells. In summary, CypA is secreted from CCA cells and enhances cell proliferation in an autocrine/paracrine manner, at least via direct binding with CD147, which may activate the ERK1/2 and p38 MAPK signaling pathways.

Cyclophilin A: A Key Factor in Virus Replication and Potential Target for Anti-viral Therapy

“…CypA acts as pro-inflammatory mediator, which stimulates inflammatory responses through CD147 (the chief cell receptor for CypA) (Yurchenko et al, 2006). It also exerts chemotactic activity for neutrophils , and human, mouse and fish leukocytes in vitro (Yeh et al, 2013;Gwinn et al 2014;Dong et al, 2015;Obchoei et al, 2015). In addition, CypA regulates the amplitude and duration of different cellular process by functioning as molecular signaling switches (Lu, et al, 2007).…”

Simvastatin attenuated rat thoracic aorta remodeling by decreasing ROCK2-mediated CyPA secretion and CD147-ERK1/2-cyclin pathway

“…CyPA has been suggested to mediate vascular remodeling by stimulating ERK1/2, VSMC growth and inflammation ( 5 , 6 ). Secreted CyPA was recently reported to mediate the G1/S phase transition of cholangiocarcinoma cells via the CD147-ERK1/2 pathway ( 10 ). Therefore, the present study further investigated alterations to downstream signaling molecules and the influence of simvastatin in the thoracic aorta.…”

“…The extracellular matrix metalloproteinase inducer basigin (CD147) was reported to be a surface receptor for extracellular CyPA ( 9 ) and mediates CyPA-specific signaling events. CyPA activates extracellular signal-regulated kinase (ERK) 1/2 via binding with CD147, leading to upregulation of cyclin D1 expression in cholangiocarcinoma cells ( 10 ). However, the kinetics of the alterations in serum CyPA and its downstream signaling cascade (CD147-ERK1/2-cyclin) during thoracic aorta remodeling have not been completely elucidated.…”

Dynamic Interaction- and Phospho-Proteomics Reveal Lck as a Major Signaling Hub of CD147 in T Cells

“…The interaction of CD147 with transporters, such as the monocarboxylate transporters 1 and 4 (MCT1 and MCT4) (3,5,16) or the amino acid transporter CD98 H chain (CD98) (54,55), has been shown to affect cell growth and survival by modulating intracellular lactate or amino acid concentrations and stimulating PI3K/PKB (3,55). The activation of PI3K/PKB and subsequent activation of the MAPK pathway upon engagement of CD147 with cyclophilins has also been observed to support cell proliferation (56,57), stress protection (23)(24)(25), and chemotactic processes (9, 26-32, 43, 58). Moreover, activation of PI3K (59) and ERK (36) were found to be prerequisites for the CD147/b1-integrin-dependent modulation of FAK activation and the adhesive capacities of cells.…”