Role of HSP90-binding immunophilins in neuroblastoma development and protection. Potential pharmacologic use of the macrolide tacrolimus

DANERI-BECERRA C, ZGAJNAR NR, CIUCCI SM, GISELA MAZAIRA GI, GALIGNIANA MD

Congreso; The 5th Intl Conference on Science, Health & Medicine; 2023

Neuroblastoma is a solid tumour formed by special nerve cells called neuroblasts. Normally, these immature cells grow into functioning nerve cells, but in neuroblastoma, they become cancer cells instead, such that they grow and divide out of control instead of developing into nerve cells. The exact cause of this abnormal growth is not known to date. Neuroblastoma usually starts in adrenal gland cells (40% of the cases), but also anywhere along the sympathetic nervous system chain from the neck to the pelvis. It is a highly metastatic disease. We established an in vitro model of apoptosis induced by exposure of neuroblastoma SH-SY5Y cells to thapsigargin, an endoplasmic reticular calcium-ATPase inhibitor, and demonstrated that FK506 (tacrolimus) protected against apoptosis. We investigated the possible correlation between the protective effect of FK506 inducible kinase (FNK) genes-which are polo-like kinases expressed abundantly in the brain by FK506. Thapsigargin increased the mRNA level of serum-inducible kinase SNK and FNK in SH-SY5Y cells. FK506 inhibited the increase in SNK mRNA but not FNK mRNA. Deletion analysis of the SNK promoter showed that the promoter site, which was regulated by thapsigargin and FK506 in a calcineurin-dependent manner, is a cAMP response element (CRE)/activating transcription factor (ATF)-like element located 84 base pairs (bp) proximal to the transcriptional initiation site. Although transcription of the SNK gene was also regulated by tunicamycin, etoposide, or staurosporine, FK506 did not show any effects on these regulations. Importantly, our studies shows that SNK is chaperoned by the Hsp90-binding immunophilin FKBP52, which is a receptor for FK506. Thus, transcriptional regulation of the SNK gene may be a biological marker for analysis of apoptosis of SH-SY5Y cells and the modulation of FKBP52 activity could have beneficial therapeutic effects.