Treatments with the selective ligand SAFit1 suggests that the Hsp90-binding immunophilin FKBP51 is a novel tumor factor

ZGAJNAR NR, GUZMÁN M, DANERI C, PATIÑO M, GALIGNIANA MD

Congreso; LXII Reunión Anual de SAIC; 2017

Immunophilins (IMMs) are a family of proteins that bind to immunosuppressive drugs and show peptidylprolyl isomerase (PPIase) activity. FKBP51 is an Hsp90-binding cochaperone able to bind the macrolide FK506, which in turn, abolishes PPIase activity. We have previously demonstrated that FKBP51 forms complexes with the reverse transcriptase subunit of telomerase, hTERT, via de molecular chaperone Hsp90. hTERT is highly expressed in cancer cells, where it is required to compensate the loss of telomeric DNA after each successive cell division, and also shows the antiapoptotic action in tumor cells. The IMM FKBP51 also shows antiapoptotic action and is overexpressed in cancer cells. Therefore, we investigated the potential anticancer activity of the IMM ligand FK506. In vitro treatment of HeLa tumor cells with FK506 decreases cell viability, possibly due to inhibition of the PPIase activity of the IMM. Importantly, in vivo treatments with FK506 of xenographic tumors generated in Squid/Nod mice significantly decreases tumor growth. Inasmuch as FK506 shows similar affinity for both IMMs FKBP51 and its close-related partner FKBP52, we tested a new synthetic drug named SAFit1, which is a potent and selective inhibitor for FKBP51. We evaluated the possible effect of this synthetic drug compared to FK506 in tumor processes, and demonstrate that SAFit1 exhibits a significant antitumor activity. Interestingly, the molecular chaperones Hsp90 and Hsp70 relocalize in the cytoplasm of drug-treated cells generating aggregation bodies that are not classified as stress granules since they do not contain the stress granule RNA-binding protein TIAR-1. Taking together, these studies confirm the hypothesis that FKBP51 is a novel antiapoptotic factor related to tumor development.