Crosstalk between Akt signaling and cold shock proteins in mediating invasive cell phenotypes
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Raphael Hohlfeld1, Sabine Brandt1, Anja Bernhardt1, Xenia Gorny1, Daniel Schindele2, Burkhard Jandrig2, Martin Schostak2, Berend Isermann3, Jonathan A. Lindquist1 and Peter R. Mertens1
1Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
2Clinic of Urology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
3Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
Peter R. Mertens, email: [email protected]
Keywords: clear cell renal cell carcinoma; cold shock proteins; YB-1; DbpA; Akt1
Received: December 22, 2017 Accepted: February 25, 2018 Published: April 10, 2018
Cold shock proteins are up-regulated by cellular stress and orchestrate inflammatory responses, cell proliferation, and differentiation. Enhanced cold shock protein expression promotes malignant cell transformation; up-regulation is detected in most cancers and associated with poor prognosis. Akt1, a serine/threonine kinase, is a potent oncogene, which activates pro-proliferative and anti-apoptotic signaling pathways, and phosphorylates the cold shock domain. Unexpectedly, chicken-YB-1 abrogates PI3K-Akt-dependent oncogenic cell transformation in embryonic fibroblasts. Here, we addressed the question whether chicken and human Y-box binding protein-1 (YB-1) act differently on cell transformation, and how a related protein, DNA-binding protein-A (DbpA) behaves in comparison. NIH3T3 cells were transduced with lentiviral vectors encoding for myristoylated (constitutive active) Akt1, YB-1, DbpA, or shRNA targeting YB-1 expression. Colony formation assays showed that human YB-1 acts similar to chicken on Akt-dependent cell transformation. This activity was not titratable. Given the correlation of nuclear YB-1 and upregulated DbpA expression in a series of clear cell renal cell carcinomas (n = 40) the colony formation assay was extended to include ectopic DbpA expression. DbpA alone prominently induced cell transformation, which was enhanced when constitutive active Akt1 or concomitant YB-1 expression was present. Notably, co-expression of DbpA together with YB-1 abrogated the repressive effect on Akt1 signaling observed with YB-1 alone. Macroscopically, some colonies yielded a remarkable “invasive” phenotype. Thus, cold shock proteins may convey profound anti- and pro-oncogenic effects on Akt-dependent cell transformation. DbpA is able to overcome the anti-oncogenic effects seen with combined YB-1 and Akt signaling in an in vitro model of colonial growth.
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