Glioblastoma cells express crucial enzymes involved in androgen synthesis: 3β‐hydroxysteroid dehydrogenase, 17‐20α‐hydroxylase, 17β‐hydroxysteroid dehydrogenase and 5α‐reductase

Abstract

Glioblastoma (GB) is the most common and aggressive primary brain tumour in adult humans. Therapeutic resistance and tumour recurrence after surgical removal contribute to poor prognosis for glioblastoma patients. Men are known to be more likely than women to develop an aggressive form of GB, and differences in sex steroids have emerged as a leading explanation for this finding. Studies indicate that the metabolism and proliferation of GB‐derived cells are increased by sex steroids, the expression of androgen receptors (ARs) and the synthesis of androgens and oestrogens, suggesting that these hormones have a role in the tumour pathogenesis. The expression of aromatase, the enzyme that converts androgens to oestrogens, has been reported in glial cells and GB cell lines. Thus, it was necessary to test whether the steroidogenic enzymes involved in androgen synthesis are expressed in GB cells. Therefore, here, we investigated the expression of four key enzymes involved in androgen synthesis in human‐derived GB cells. U87 cells were cultured in Dulbecco's modified Eagle medium plus foetal bovine serum and antibiotics on slides for immunocytochemistry or immunofluorescence. U87, LN229 and C6 cells were also cultured in multi‐well chambers to obtain proteins for Western blotting. We used primary antibodies against 3β‐hydroxysteroid dehydrogenase (3β‐HSD), 17α‐hydroxilase/17,20‐lyase (P450c17), 17β‐hydroxysteroid dehydrogenase (17β‐HSD) and 5α‐reductase. Immunocytochemistry, and immunofluorescence results revealed that glioblastoma cells express 3β‐HSD, P450c17, 17β‐HSD and 5α‐reductase proteins in their cytoplasm. Moreover, Western blot analyses revealed bands corresponding to the molecular weight of these four enzymes in the three GB cell lines. Thus, glioblastoma cells have the key enzymatic machinery necessary to synthesize androgens, and these enzymes might be useful targets for new therapeutic approaches.

Proteomic and metabolomic signatures of U87 glioblastoma cells treated with cisplatin and/or paclitaxel

“…This is significant because immune cells that infiltrate cancer cells can lead to the production of cytokines, which in turn stimulates aromatase activity [ 86 ] ( Figure 10 ). Moreover, U87 cells retain steroidogenic enzymes in glial cells, such as 17-20α-hydroxylase, 17β-hydroxysteroid dehydrogenase and 5α-reductase [ 87 ], equipping U87 cells with the machinery required to synthesize androgens and other neurosteroids that may be involved in the formation of GBM [ 87 ]. Recently, it was reported that microglia can synthesize androstenediones [ 88 ].…”

The Next Frontier in Health Disparities—A Closer Look at Exploring Sex Differences in Glioma Data and Omics Analysis, from Bench to Bedside and Back

“…Given that male vs. female tumor incidence in glioma varies by tumor subtype, region, and age, with males exhibiting a 20–40% higher incidence of CNS (Central Nervous System) tumors in young adults [ 4 ], and with treatment received intersecting with risk factors for death, gender [ 5 ], and age [ 6 , 7 ], significant intersectionality is expected when analyzing disparities and unbalanced data sets. In the context of glioma, several papers have explored biological factors and sex-dependent differences between men and women and implications related to histology, sex hormones [ 8 , 9 ], pregnancy, menstruation, menopause, and oral contraceptives. There is, however, an ongoing lack of in-depth understanding of the physiology and metabolism that underpins sex differences in glioma, with data just emerging [ 3 , 8 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”