Ferroptosis inducer erastin downregulates androgen receptor and its splice variants in castration‑resistant prostate cancer

Yang,Yanrong; Liu,Taiyuan; Hu,Cheng; Xia,Hongyan; Liu,Wei; Chen,Junyu; Wu,Shan; Jiang,Yu; Xu,Yang; Liu,Wanxia; Zhao,Lijing

doi:10.3892/or.2021.7976

Ferroptosis inducer erastin downregulates androgen receptor and its splice variants in castration‑resistant prostate cancer

Authors:
- Yanrong Yang
- Taiyuan Liu
- Cheng Hu
- Hongyan Xia
- Wei Liu
- Junyu Chen
- Shan Wu
- Yu Jiang
- Yang Xu
- Wanxia Liu
- Lijing Zhao
View Affiliations

Affiliations: Department of Recovery, Nursing School, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Breast Surgery, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China, Department of National Engineering Laboratory for AIDS Vaccine, College of Life Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Analysis and Testing Center, Jilin Academy of Environmental Sciences, Changchun, Jilin 130021, P.R. China, Department of Gynaecology and Obstetrics, The Second Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: February 15, 2021 https://doi.org/10.3892/or.2021.7976
Article Number: 25

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

To date, there is no effective therapy available for the treatment of castration‑resistant prostate cancer (CRPC), and patients generally succumb to the disease within 2 to 4 years. In the progression of CRPC, androgen receptor (AR) and its splice variants play critical roles. Hence, it is necessary to develop a drug to inhibit the expression and activity of the full‑length and splice variants of AR for the treatment of CRPC. Erastin, as the first discovered drug to induce ferroptosis, has been studied in various types of cancer. However, there are few studies focusing on the relationship between erastin and AR. In the present study, western blotting, and sulforhodamine B cell viability, glutathione, lipid peroxidation and reactive oxygen species assays were performed to verify the ferroptosis of CRPC cells; reverse transcription‑quantitative polymerase chain reaction, dual‑luciferase reporter, and lentiviral packaging and lentivirus‑infected cell assays were employed to evaluate how erastin affects AR. A mouse xenograft assay was used to determine the underlying mechanism in vivo. Erastin, as a classical inducer of ferroptosis, can suppress the transcriptional activities of both the full‑length and splice variants in AR models in vitro and in vivo. In addition, when erastin was used for CRPC treatment combined with docetaxel, the growth inhibitory efficacy of docetaxel was found to be enhanced. Thus, these findings indicated that ferroptosis inducer erastin has potential in the treatment of CRPC via targeting AR.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Ferraldeschi R, Welti J, Luo J, Attard G and de Bono JS: Targeting the androgen receptor pathway in castration-resistant prostate cancer: Progresses and prospects. Oncogene. 34:1745–1757. 2015. View Article : Google Scholar : PubMed/NCBI
3	Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, et al: Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest. 120:2715–2730. 2010. View Article : Google Scholar : PubMed/NCBI
4	Noble RL: The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. Cancer Res. 37:1929–1933. 1977.PubMed/NCBI
5	Egan A, Dong Y, Zhang H, Qi Y, Balk SP and Sartor O: Castration-resistant prostate cancer: Adaptive responses in the androgen axis. Cancer Treat Rev. 40:426–433. 2014. View Article : Google Scholar : PubMed/NCBI
6	Centenera MM, Harris JM, Tilley WD and Butler LM: The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol Endocrinol. 22:2373–2382. 2008. View Article : Google Scholar : PubMed/NCBI
7	Chandrasekar T, Yang JC, Gao AC and Evans CP: Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 4:365–380. 2015.PubMed/NCBI
8	Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL, Isaacs WB, et al: Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 69:16–22. 2009. View Article : Google Scholar : PubMed/NCBI
9	Dolma S, Lessnick SL, Hahn WC and Stockwell BR: Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 3:285–296. 2003. View Article : Google Scholar : PubMed/NCBI
10	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI
11	Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, et al: RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 447:864–868. 2007. View Article : Google Scholar : PubMed/NCBI
12	Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti NP, Slusher BS and Stockwell BR: Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 3:e025232014. View Article : Google Scholar : PubMed/NCBI
13	Sato M, Kusumi R, Hamashima S, Kobayashi S, Sasaki S, Komiyama Y, Izumikawa T, Conrad M, Bannai S and Sato H: The ferroptosis inducer erastin irreversibly inhibits system xc- and synergizes with cisplatin to increase cisplatin's cytotoxicity in cancer cells. Sci Rep. 8:9682018. View Article : Google Scholar : PubMed/NCBI
14	Yu Y, Xie Y, Cao L, Yang L, Yang M, Lotze MT, Zeh HJ, Kang R and Tang D: The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol. 2:e10545492015. View Article : Google Scholar : PubMed/NCBI
15	Kwon MY, Park E, Lee SJ and Chung SW: Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget. 6:24393–24403. 2015. View Article : Google Scholar : PubMed/NCBI
16	Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R and Tang D: Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 63:173–184. 2016. View Article : Google Scholar : PubMed/NCBI
17	Hasegawa M, Takahashi H, Rajabi H, Alam M, Suzuki Y, Yin L, Tagde A, Maeda T, Hiraki M, Sukhatme VP and Kufe D: Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. Oncotarget. 7:11756–11769. 2016. View Article : Google Scholar : PubMed/NCBI
18	Roh JL, Kim EH, Jang HJ, Park JY and Shin D: Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 381:96–103. 2016. View Article : Google Scholar : PubMed/NCBI
19	Dong Y, Zhang H, Hawthorn L, Ganther HE and Ip C: Delineation of the molecular basis for selenium-induced growth arrest in human prostate cancer cells by oligonucleotide array. Cancer Res. 63:52–59. 2003.PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Gordon CA, Gulzar ZG and Brooks JD: NUSAP1 expression is upregulated by loss of RB1 in prostate cancer cells. Prostate. 75:517–526. 2015. View Article : Google Scholar : PubMed/NCBI
22	Wu S, Zhao F, Zhao J, Li H, Chen J, Xia Y, Wang J, Zhao B, Zhao S and Li N: Dioscin improves postmenopausal osteoporosis through inducing bone formation and inhibiting apoptosis in ovariectomized rats. Biosci Trends. 13:394–401. 2019. View Article : Google Scholar : PubMed/NCBI
23	Zheng J, Zhao S, Yu X, Huang S and Liu HY: Simultaneous targeting of CD44 and EpCAM with a bispecific aptamer effectively inhibits intraperitoneal ovarian cancer growth. Theranostics. 7:1373–1388. 2017. View Article : Google Scholar : PubMed/NCBI
24	Dehm SM, Schmidt LJ, Heemers HV, Vessella RL and Tindall DJ: Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 68:5469–5477. 2008. View Article : Google Scholar : PubMed/NCBI
25	Kita K, Shiota M, Tanaka M, Otsuka A, Matsumoto M, Kato M, Tamada S, Iwao H, Miura K, Nakatani T and Tomita S: Heat shock protein 70 inhibitors suppress androgen receptor expression in LNCaP95 prostate cancer cells. Cancer Sci. 108:1820–1827. 2017. View Article : Google Scholar : PubMed/NCBI
26	Zhao N, Peacock SO, Lo CH, Heidman LM, Rice MA, Fahrenholtz CD, Greene AM, Magani F, Copello VA, Martinez MJ, et al: Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer. Sci Transl Med. 11:eaaw46362019. View Article : Google Scholar : PubMed/NCBI
27	Xu D, Zhan Y, Qi Y, Cao B, Bai S, Xu W, Gambhir SS, Lee P, Sartor O, Flemington EK, et al: Androgen receptor splice variants dimerize to transactivate target genes. Cancer Res. 75:3663–3671. 2015. View Article : Google Scholar : PubMed/NCBI
28	Paschalis A, Sharp A, Welti JC, Neeb A, Raj GV, Luo J, Plymate SR and de Bono JS: Alternative splicing in prostate cancer. Nat Rev Clin Oncol. 15:663–675. 2018. View Article : Google Scholar : PubMed/NCBI
29	Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, Corey E, Nanus DM, Plymate SR and Giannakakou P: Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 74:2270–2282. 2014. View Article : Google Scholar : PubMed/NCBI
30	Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, Gjyrezi A, Chanel-Vos C, Shen R, Tagawa ST, et al: Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res. 71:6019–6029. 2011. View Article : Google Scholar : PubMed/NCBI
31	Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM and Kyprianou N: Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res. 70:7992–8002. 2010. View Article : Google Scholar : PubMed/NCBI
32	Bai S, Zhang BY and Dong Y: Impact of taxanes on androgen receptor signaling. Asian J Androl. 21:249–252. 2019. View Article : Google Scholar : PubMed/NCBI
33	Zhao Y, Li Y, Zhang R, Wang F, Wang T and Jiao Y: The role of erastin in ferroptosis and its prospects in cancer therapy. Onco Targets Ther. 13:5429–5441. 2020. View Article : Google Scholar : PubMed/NCBI
34	Huo H, Zhou Z, Qin J, Liu W, Wang B and Gu Y: Erastin disrupts mitochondrial permeability transition pore (mPTP) and induces apoptotic death of colorectal cancer cells. PLoS One. 11:e01546052016. View Article : Google Scholar : PubMed/NCBI
35	Yu M, Gai C, Li Z, Ding D, Zheng J, Zhang W, Lv S and Li W: Targeted exosome-encapsulated erastin induced ferroptosis in triple negative breast cancer cells. Cancer Sci. 110:3173–3182. 2019. View Article : Google Scholar : PubMed/NCBI
36	Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 371:1028–1038. 2014. View Article : Google Scholar : PubMed/NCBI
37	Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA and Dehm SM: Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 73:483–489. 2013. View Article : Google Scholar : PubMed/NCBI
38	Ponnusamy S, Coss CC, Thiyagarajan T, Watts K, Hwang DJ, He Y, Selth LA, McEwan IJ, Duke CB, Pagadala J, et al: Novel selective agents for the degradation of androgen receptor variants to treat castration-resistant prostate cancer. Cancer Res. 77:6282–6298. 2017. View Article : Google Scholar : PubMed/NCBI
39	Yamashita S, Lai KP, Chuang KL, Xu D, Miyamoto H, Tochigi T, Pang ST, Li L, Arai Y, Kung HJ, et al: ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors. Neoplasia. 14:74–83. 2012. View Article : Google Scholar : PubMed/NCBI
40	Zhang G, Liu X, Li J, Ledet E, Alvarez X, Qi Y, Fu X, Sartor O, Dong Y and Zhang H: Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents. Oncotarget. 6:23358–23371. 2015. View Article : Google Scholar : PubMed/NCBI
41	Shan X, Danet-Desnoyers G, Aird F, Kandela I, Tsui R, Perfito N and Iorns E: Replication study: Androgen receptor splice variants determine taxane sensitivity in prostate cancer. PeerJ. 6:e46612018. View Article : Google Scholar : PubMed/NCBI
42	Cristofani R, Montagnani Marelli M, Cicardi ME, Fontana F, Marzagalli M, Limonta P, Poletti A and Moretti RM: Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells. Cell Death Dis. 9:8892018. View Article : Google Scholar : PubMed/NCBI
43	Wang L, Chen H, Liu F, Madigan MC, Power CA, Hao J, Patterson KI, Pourgholami MH, O'Brien PM, Perkins AC and Li Y: Monoclonal antibody targeting MUC1 and increasing sensitivity to docetaxel as a novel strategy in treating human epithelial ovarian cancer. Cancer Lett. 300:122–133. 2011. View Article : Google Scholar : PubMed/NCBI
44	Zhang D, Cui Y, Niu L, Xu X, Tian K, Young CYF, Lou H and Yuan H: Regulation of SOD2 and β-arrestin1 by interleukin-6 contributes to the increase of IGF-1R expression in docetaxel resistant prostate cancer cells. Eur J Cell Biol. 93:289–298. 2014. View Article : Google Scholar : PubMed/NCBI
45	Shan W, Zhong W, Zhao R and Oberley TD: Thioredoxin 1 as a subcellular biomarker of redox imbalance in human prostate cancer progression. Free Radic Biol Med. 49:2078–2087. 2010. View Article : Google Scholar : PubMed/NCBI