Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance.
Results:
Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and in vivo. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment.
Conclusion and Innovation:
We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 42, 954–972.
Get full access to this article
View all access options for this article.
References
1.
AnJ, ZhangY, HeJ, et al.Lactate dehydrogenase A promotes the invasion and proliferation of pituitary adenoma. Sci Rep, 2017; 7(1):4734; doi: 10.1038/s41598-017-04366-5
2.
BazuhairT, AleidB, AlmalkiM. Effect of tamoxifen on the management of dopamine agonist-resistant prolactinomas: A systematic review. Cureus, 2023; 15(2):e35171; doi: 10.7759/cureus.35171
3.
ChangC, LeeSO, YehS, et al.Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogene, 2014; 33(25):3225–3234; doi: 10.1038/onc.2013.274
4.
ChengY, DaiY, TangH, et al.Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors. Acta Neuropathol Commun, 2024; 12(1):61; doi: 10.1186/s40478-024-01775-2
5.
ChirnomasD, HornbergerKR, CrewsCM. Protein degraders enter the clinic - a new approach to cancer therapy. Nat Rev Clin Oncol, 2023; 20(4):265–278; doi: 10.1038/s41571-023-00736-3
6.
ChoupaniE, Mahmoudi GomariM, ZanganehS, et al.Newly developed targeted therapies against the androgen receptor in triple-negative breast cancer: A review. Pharmacol Rev, 2023; 75(2):309–327; doi: 10.1124/pharmrev.122.000665
7.
ClocchiattiA, CoraE, ZhangY, et al.Sexual dimorphism in cancer. Nat Rev Cancer, 2016; 16(5):330–339; doi: 10.1038/nrc.2016.30
8.
CochraneDR, BernalesS, JacobsenBM, et al.Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res, 2014; 16(1):R7; doi: 10.1186/bcr3599
9.
DayFP, GlereanM, LovazzanoS, et al.Gender differences in macroprolactinomas: Study of clinical features, outcome of patients and ki-67 expression in tumor tissue. Front Horm Res, 2010; 38:50–58; doi: 10.1159/000318494
10.
De AmicisF, ThirugnansampanthanJ, CuiY, et al.Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat, 2010; 121(1):1–11; doi: 10.1007/s10549-009-0436-8
11.
DelgrangeE, VasiljevicA, WierinckxA, et al.Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth. Eur J Endocrinol, 2015; 172(6):791–801; doi: 10.1530/EJE-14-0990
12.
DeNicolaGM, KarrethFA, HumptonTJ, et al.Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature, 2011; 475(7354):106–109; doi: 10.1038/nature10189
GorriniC, HarrisIS, MakTW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov, 2013; 12(12):931–947; doi: 10.1038/nrd4002
15.
HayesJD, Dinkova-KostovaAT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci, 2014; 39(4):199–218; doi: 10.1016/j.tibs.2014.02.002
16.
HayesJD, Dinkova-KostovaAT, TewKD. Oxidative stress in cancer. Cancer Cell, 2020; 38(2):167–197; doi: 10.1016/j.ccell.2020.06.001
17.
HuB, MaoZ, DuQ, et al.miR-93-5p targets Smad7 to regulate the transforming growth factor-beta1/Smad3 pathway and mediate fibrosis in drug-resistant prolactinoma. Brain Res Bull, 2019; 149:21–31; doi: 10.1016/j.brainresbull.2019.03.013
18.
HuB, MaoZ, JiangX, et al.Role of TGF-beta1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma. Brain Res, 2018; 1698:204–212; doi: 10.1016/j.brainres.2018.07.024
19.
HuC, FangD, XuH, et al.The androgen receptor expression and association with patient’s survival in different cancers. Genomics, 2020; 112(2):1926–1940; doi: 10.1016/j.ygeno.2019.11.005
20.
HuM, ZhangY, LuL, et al.Overactivation of the androgen receptor exacerbates gravid uterine ferroptosis via interaction with and suppression of the NRF2 defense signaling pathway. FEBS Lett, 2022; 596(6):806–825; doi: 10.1002/1873-3468.14289
21.
Jaffrain-ReaML, PetrangeliE, OrtolaniF, et al.Cellular receptors for sex steroids in human pituitary adenomas. J Endocrinol, 1996; 151(2):175–184; doi: 10.1677/joe.0.1510175
22.
JaubertA, IchasF, Bresson-BepoldinL. Signaling pathway involved in the pro-apoptotic effect of dopamine in the GH3 pituitary cell line. Neuroendocrinology, 2006; 83(2):77–88; doi: 10.1159/000094044
23.
KonoM, FujiiT, LimB, et al.Androgen receptor function and androgen receptor-targeted therapies in breast cancer: A review. JAMA Oncol, 2017; 3(9):1266–1273; doi: 10.1001/jamaoncol.2016.4975
24.
LeiG, ZhuangL, GanB. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer, 2022; 22(7):381–396; doi: 10.1038/s41568-022-00459-0
25.
LengZG, LinSJ, WuZR, et al.Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death. Autophagy, 2017; 13(8):1404–1419; doi: 10.1080/15548627.2017.1328347
26.
LeoJ, DondossolaE, BashamKJ, et al.Stranger things: New roles and opportunities for androgen receptor in oncology beyond prostate cancer. Endocrinology, 2023; 164(6); doi: 10.1210/endocr/bqad071
27.
LiD, ZhouW, PangJ, et al.A magic drug target: Androgen receptor. Med Res Rev, 2019; 39(5):1485–1514; doi: 10.1002/med.21558
28.
LiF, XingX, JinQ, et al.Sex differences orchestrated by androgens at single-cell resolution. Nature, 2024; 629(8010):193–200; doi: 10.1038/s41586-024-07291-6
29.
LiN, ZhanX. Mitochondrial dysfunction pathway networks and mitochondrial dynamics in the pathogenesis of pituitary adenomas. Front Endocrinol (Lausanne), 2019; 10:690; doi: 10.3389/fendo.2019.00690
30.
LiZ, LiuQ, LiC, et al.The role of TGF-β/Smad signaling in dopamine agonist-resistant prolactinomas. Mol Cell Endocrinol, 2015; 402:64–71; doi: 10.1016/j.mce.2014.12.024
31.
LiuX, TangC, WenG, et al.The mechanism and pathways of dopamine and dopamine agonists in prolactinomas. Front Endocrinol (Lausanne), 2018; 9:768; doi: 10.3389/fendo.2018.00768
MatsumotoT, SakariM, OkadaM, et al.The androgen receptor in health and disease. Annu Rev Physiol, 2013; 75:201–224; doi: 10.1146/annurev-physiol-030212-183656
34.
Mauvais-JarvisF, Bairey MerzN, BarnesPJ, et al.Sex and gender: Modifiers of health, disease, and medicine. Lancet, 2020; 396(10250):565–582; doi: 10.1016/S0140-6736(20)31561-0
PalmeriCM, PetitiJP, SosaLV, et al.Bromocriptine induces parapoptosis as the main type of cell death responsible for experimental pituitary tumor shrinkage. Toxicol Appl Pharmacol, 2009; 240(1):55–65; doi: 10.1016/j.taap.2009.07.002
37.
PellegriniI, RasolonjanaharyR, GunzG, et al.Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab, 1989; 69(3):500–509; doi: 10.1210/jcem-69-3-500
38.
PetersennS, FleseriuM, CasanuevaFF, et al.Diagnosis and management of prolactin-secreting pituitary adenomas: A Pituitary Society International Consensus Statement. Nat Rev Endocrinol, 2023; 19(12):722–740; doi: 10.1038/s41574-023-00886-5
39.
RecouvreuxMV, CamillettiMA, RifkinDB, et al.The pituitary TGFbeta1 system as a novel target for the treatment of resistant prolactinomas. J Endocrinol, 2016; 228(3):R73–R83; doi: 10.1530/JOE-15-0451
40.
Rodriguez-LozanoDC, Pina-MedinaAG, Hansberg-PastorV, et al.Testosterone promotes glioblastoma cell proliferation, migration, and invasion through androgen receptor activation. Front Endocrinol (Lausanne), 2019; 10:16; doi: 10.3389/fendo.2019.00016
41.
Rojo de la VegaM, ChapmanE, ZhangDD. NRF2 and the Hallmarks of Cancer. Cancer Cell, 2018; 34(1):21–43; doi: 10.1016/j.ccell.2018.03.022
42.
RushworthSA, ZaitsevaL, MurrayMY, et al.The high Nrf2 expression in human acute myeloid leukemia is driven by NF-kappaB and underlies its chemo-resistance. Blood, 2012; 120(26):5188–5198; doi: 10.1182/blood-2012-04-422121
43.
SabatinoME, GrondonaE, SosaDVL, et al.Oxidative stress and mitochondrial adaptive shift during pituitary tumoral growth. Free Radic Biol Med, 2018; 120:41–55; doi: 10.1016/j.freeradbiomed.2018.03.019
44.
SaegerW, SchreiberS, LudeckeDK. Androgen receptor in pituitary adenomas of the gonadotroph cell complex. Pathol Res Pract, 2000; 196(11):771–773; doi: 10.1016/S0344-0338(00)80110-7
45.
ScheithauerBW, KovacsK, ZorludemirS, et al.Immunoexpression of androgen receptor in the nontumorous pituitary and in adenomas. Endocr Pathol, 2008; 19(1):27–33; doi: 10.1007/s12022-007-9012-0
46.
SharpeMA, BaskinDS, JensonAV, et al.Hijacking sexual immuno-privilege in GBM-An immuno-evasion strategy. Int J Mol Sci, 2021; 22(20); doi: 10.3390/ijms222010983
47.
ShimazuS, ShimatsuA, YamadaS, et al.Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels. Eur J Endocrinol, 2012; 166(3):383–390; doi: 10.1530/eje-11-0656
48.
SiesH, JonesDP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol, 2020; 21(7):363–383; doi: 10.1038/s41580-020-0230-3
TorrenteL, DeNicolaGM. Targeting NRF2 and Its downstream processes: Opportunities and challenges. Annu Rev Pharmacol Toxicol, 2022; 62(1):279–300; doi: 10.1146/annurev-pharmtox-052220-104025
54.
TritosNA, MillerKK. Diagnosis and management of pituitary adenomas: A review. JAMA, 2023; 329(16):1386–1398; doi: 10.1001/jama.2023.5444
55.
VroonenL, DalyAF, BeckersA. Epidemiology and management challenges in prolactinomas. Neuroendocrinology, 2019; 109(1):20–27; doi: 10.1159/000497746
56.
VroonenL, Jaffrain-ReaML, PetrossiansP, et al.Prolactinomas resistant to standard doses of cabergoline: A multicenter study of 92 patients. Eur J Endocrinol, 2012; 167(5):651–662; doi: 10.1530/EJE-12-0236
57.
WanX, YanZ, TanZ, et al.MicroRNAs in dopamine agonist-resistant prolactinoma. Neuroendocrinology, 2022; 112(5):417–426; doi: 10.1159/000517356
58.
WangD, WongHK, FengYB, et al.18beta-glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. J Neurooncol, 2014; 116(2):221–230; doi: 10.1007/s11060-013-1292-2
59.
WangY, ChenJ, WuZ, et al.Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it. Br J Pharmacol, 2021; 178(2):239–261; doi: 10.1111/bph.15300
60.
WangY, PangB, ZhangR, et al.Ubenimex induces apoptotic and autophagic cell death in rat GH3 and MMQ cells through the ROS/ERK pathway. Drug Des Devel Ther, 2019; 13:3217–3228; doi: 10.2147/dddt.S218371
61.
WatsonPA, AroraVK, SawyersCL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer, 2015; 15(12):701–711; doi: 10.1038/nrc4016
62.
WernerCK, NnaUJ, SunH, et al.Expression of the androgen receptor governs radiation resistance in a subset of glioblastomas vulnerable to antiandrogen therapy. Mol Cancer Ther, 2020; 19(10):2163–2174; doi: 10.1158/1535-7163.MCT-20-0095
63.
WierinckxA, DelgrangeE, BertolinoP, et al.Sex-Related differences in lactotroph tumor aggressiveness are associated with a specific gene-expression signature and genome instability. Front Endocrinol (Lausanne), 2018; 9:706; doi: 10.3389/fendo.2018.00706
64.
WuN, ZhuD, LiJ, et al.CircOMA1 modulates cabergoline resistance by downregulating ferroptosis in prolactinoma. J Endocrinol Invest, 2023; 46(8):1573–1587; doi: 10.1007/s40618-023-02010-w
65.
WuZ, XuY, XuJ, et al.Brusatol inhibits tumor growth and increases the efficacy of cabergoline against pituitary adenomas. Oxid Med Cell Longev, 2021; 2021:6696015; doi: 10.1155/2021/6696015
66.
YinD, TamakiN, KokunaiT, et al.Bromocriptine-induced apoptosis in pituitary adenoma cells: Relationship to p53 and bcl-2 expression. J Clin Neurosci, 1999; 6(4):326–331; doi: 10.1054/jocn.1998.0063
67.
ZhangSL, TangHB, HuJT, et al.PGAM5-CypD pathway is involved in bromocriptine-induced RIP3/MLKL-dependent necroptosis of prolactinoma cells. Biomed Pharmacother, 2019; 111:638–648; doi: 10.1016/j.biopha.2018.12.128
68.
ZhangZ, BartschJW, BenzelJ, et al.Selective estrogen receptor modulators decrease invasiveness in pituitary adenoma cell lines AtT-20 and TtT/GF by affecting expression of MMP-14 and ADAM12. FEBS Open Bio, 2020; 10(11):2489–2498; doi: 10.1002/2211-5463.12999
69.
ZhouY, ZhangA, FangC, et al.Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy. CNS Neurosci Ther, 2023; 29(10):2744–2759; doi: 10.1111/cns.14315
70.
ZhuJ, TangC, CongZ, et al.ACT001 reverses resistance of prolactinomas via AMPK-mediated EGR1 and mTOR pathways. Endocr Relat Cancer, 2021; 29(2):33–46; doi: 10.1530/ERC-21-0215
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
