IMMUNOPHILIN FKBP51 SHOWS ONCOGENIC PROPERTIES IN A GLIOBLASTOMA CELL LINE

CAMILA G. SZCZEPANIK, MARÍA E. ROSBACO, NADIA ZGAJNAR, MARIO D. GALIGNIANA

Congreso; LXVIII REUNIÓN ANUAL DE SAIC; 2023

Immunophilins belong to the molecular chaperone family, constituting a subfamily of proteins that exhibit two specific properties: they show peptidylprolyl-(cis/trans)-isomerase activity and the capacity to bind immunosuppressive drugs. FKBP51 (FK506-Binding Protein of 51-kDa) is an Hsp90-binding immunophilin that was first discovered associated with steroid receptor heterocomplexes via its interaction with Hsp90. Recently, our laboratory discovered that FKBP51 is also a mitochondrial factor that shows antiapoptotic properties in normal fibroblasts. In this study, it is shown that FKBP51 is transported from mitochondria to the nucleus upon the onset of any type of stress (temperature, oxidative stress, toxins, etc.). This led us to think that in highly stressed cells such as cancer cells, FKBP51 should also show a predominantly nuclear localization. This was evidenced by confocal microscopy in several cancer cell lines, including N2a murine neuroblastoma cells and U87 human glioma cells. Also, Western blot analysis revealed that FKBP51 is overexpressed in all cancer cell lines compared to normal cell lines. To confirm this, NIH-3T3 fibroblasts were transformed into a tumorigenic cell line by transfection of the v-Ha-Ras oncogene. The transformed cells acquired a malignant phenotype, FKBP51 being mostly nuclear rather than mitochondrial and highly expressed. Inasmuch as TERT, the catalytic subunit of telomerase, is abundant in cancer cells and a known client factor of Hsp90, the recruitment of FKBP51 was investigated in U87 human glioma cells. Co-immuno-precipitation assays demonstrated the presence of FKBP51 in TERT•Hsp90 complexes, an oligomer that was disrupted by the Hsp90 inhibitor geldanamycin. Importantly, the overexpression of FKBP51 enhanced telomerase enzymatic activity. Based on these findings, we propose that a U87 glioma cell model could be useful to elucidate the role of FKBP51 role in glioblastoma development and progression.