Overexpression of 17β-hydroxysteroid dehydrogenase type 10 increases pheochromocytoma cell growth and resistance to cell death

Abstract

Background17β-hydroxysteroid dehydrogenase type 10 (HSD10) has been shown to play a protective role in cells undergoing stress. Upregulation of HSD10 under nutrient-limiting conditions leads to recovery of a homeostatic state. Across disease states, increased HSD10 levels can have a profound and varied impact, such as beneficial in Parkinson’s disease and harmful in Alzheimer’s disease. Recently, HSD10 overexpression has been observed in some prostate and bone cancers, consistently correlating with poor patient prognosis. As the role of HSD10 in cancer remains underexplored, we propose that cancer cells utilize this enzyme to promote cancer cell survival under cell death conditions.MethodsThe proliferative effect of HSD10 was examined in transfected pheochromocytoma cells by growth curve analysis and a xenograft model. Fluctuations in mitochondrial bioenergetics were evaluated by electron transport chain complex enzyme activity assays and energy production. Additionally, the effect of HSD10 on pheochromocytoma resistance to cell death was investigated using TUNEL staining, MTT, and complex IV enzyme activity assays.ResultsIn this study, we examined the tumor-promoting effect of HSD10 in pheochromocytoma cells. Overexpression of HSD10 increased pheochromocytoma cell growth in both in vitro cell culture and an in vivo xenograft mouse model. The increases in respiratory enzymes and energy generation observed in HSD10-overexpressing cells likely supported the accelerated growth rate observed. Furthermore, cells overexpressing HSD10 were more resistant to oxidative stress-induced perturbation.ConclusionsOur findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction. This suggests that blockade of HSD10 may halt and/or prevent cancer growth, thus providing a promising novel target for cancer patients as a screening or therapeutic option.

Interactions of 17β-Hydroxysteroid Dehydrogenase Type 10 and Cyclophilin D in Alzheimer's Disease

“…6). This can be interpreted via Aβ-related dysbalance in levels of mitochondrial 17β-HSD10 and cypD and via trend to dysbalance among various complexes of 17β-HSD10 which can finally lead to the weakened function of 17β-HSD10 to regulate cypD in the matrix, in accordance with literature [20]. It seems that especially some fragments of accumulated Aβ via its enhanced binding to 17β-HSD10 could eliminate the interaction of 17β-HSD10 and cypD [40] and thus decrease the levels of 17β-HSD10-cypD complexes in the matrix.…”

“…Free cypD could consequently translocate to the inner mitochondrial membrane and open MPTP. It is well known that MPTP opening results in inner membrane potential collapse, respiratory chain uncoupling, halt of mitochondrial adenosine triphosphate synthesis, and eventually mitochondrial swelling, rupture, and cell death [20]. We thus suggest that the weakened function of 17β-HSD10 to regulate cypD in the mitochondrial matrix can be directly involved in mitochondrial dysfunction.…”

“…It was hypothesised that 17β-HSD10 in the mitochondrial matrix binds to cyclophilin D (cypD) and that by preventing its translocation to the inner mitochondrial membrane it can regulate the opening of the mitochondrial permeability transition pore (MPTP) mediated by cypD [20]. Although interactions of 17β-HSD10 and cypD were predicted indirectly by co-immunoprecipitation and colocalization [20], the binding between 17β-HSD10 and cypD has not yet been confirmed experimentally.…”

“…It was hypothesised that 17β-HSD10 in the mitochondrial matrix binds to cyclophilin D (cypD) and that by preventing its translocation to the inner mitochondrial membrane it can regulate the opening of the mitochondrial permeability transition pore (MPTP) mediated by cypD [20]. Although interactions of 17β-HSD10 and cypD were predicted indirectly by co-immunoprecipitation and colocalization [20], the binding between 17β-HSD10 and cypD has not yet been confirmed experimentally. On the other hand, previous data found mutual interactions of cypD and Aβ in direct experiments in vitro using surface plasmon resonance (SPR) biosensor, and their co-localization in cortical mitochondria of AD patients and Tg animal models of AD [17,21,22].…”

A chemical genomics approach to drug reprofiling in oncology: Antipsychotic drug risperidone as a potential adenocarcinoma treatment

“…Recently, it has become apparent that 17HSD10 is overexpressed in many cancerous cells, particularly those of adenocarcinoma types [17], with the enzyme s multifunctional nature contributing more broadly to the stabilisation of cancer cells [18].…”