Abstract
Cytochrome P450 (CYP) 17A1 is an important steroidogenic enzyme harboring 17α-hydroxylase and performing 17,20 lyase activities in multiple steps of steroid hormone synthesis, including dehydroepiandrosterone (DHEA) biosynthesis. Previously, we showed that CYP17A1-mediated DHEA production clearly protects glioblastomas from temozolomide-induced apoptosis, leading to drug resistance. Herein, we attempt to clarify whether the inhibition of CYP17A1 has a tumor-suppressive effect, and to determine the steroidogenesis-independent functions of CYP17A1 in glioblastomas. Abiraterone, an inhibitor of CYP17A1, significantly inhibits the proliferation of A172, T98G, and PT#3 (the primary glioblastoma cells) by inducing apoptosis. In parallel, abiraterone potently suppresses tumor growth in mouse models through transplantation of PT#3 cells to the back or to the brain. Based on evidence that abiraterone induces endoplasmic reticulum (ER) stress, followed by the accumulation of reactive oxygen species (ROS), CYP17A1 is important for ER health and redox homeostasis. To confirm our hypothesis, we showed that CYP17A1 overexpression prevents the initiation of ER stress and attenuates ROS production by regulating SAR1a/b expression. Abiraterone dissociates SAR1a/b from ER-localized CYP17A1, and induces SAR1a/b ubiquitination, leading to degradation. Furthermore, SAR1 overexpression rescues abiraterone-induced apoptosis and impairs redox homeostasis. In addition to steroid hormone synthesis, CYP17A1 associates with SAR1a/b to regulate protein processing and maintain ER health in glioblastomas.
Highlights
Steroidogenesis-mediated neurosteroid production is important for the maintenance of brain health, including synapse formation, neural survival, and astrocyte proliferation [1,2,3,4]
We showed that CYP17A1 upregulation confers drug resistance to glioblastomas by increasing DHEA synthesis [7,8]
We found that intravenous administration with abiraterone (20 mg/kg) significantly inhibited the growth of tumors, which were subcutaneously xenografted with PT#3 cells on the back (Figure 1B)
Summary
Steroidogenesis-mediated neurosteroid production is important for the maintenance of brain health, including synapse formation, neural survival, and astrocyte proliferation [1,2,3,4]. Neurosteroids protect brain cells against stress, such as oxidative stress and glutamate cytotoxicity [5,6]. Cancers 2019, 11, 1378 brain tumors are protected by neurosteroids, attenuating the therapeutic effect of chemotherapy. We found that dehydroepiandrosterone (DHEA), a kind of neurosteroid, protects glioma cells from chemotherapy-induced apoptosis, leading to drug resistance [7,8]. The upregulation of DHEA in gliomas is caused by Sp1-mediated cytochrome P450 (CYP) 17A1 overexpression [7], implying that CYP17A1 is a potential target for glioma treatment.
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