TXNDC9 regulates oxidative stress-induced androgen receptor signaling to promote prostate cancer progression

Abstract

Reactive oxygen species (ROS) and ROS-induced oxidative stress are associated with prostate cancer (PCa) development and castrate-resistant tumor progression. This is in part through the activation of the androgen receptor (AR) signaling. However, the molecular underpinning of ROS to activate AR remains poorly understood. Here, we report that the thioredoxin domain-containing 9 (TXNDC9) is an important regulator of ROS to trigger AR signaling. TXNDC9 expression is upregulated by ROS inducer, and increased TXNDC9 expression in patient tumors is associated with advanced clinical stages. TXNDC9 promotes PCa cell survival and proliferation. It is required for AR protein expression and AR transcriptional activity under oxidative stress conditions. Mechanistically, ROS inducers promote TXNDC9 to dissociate from PRDX1, but enhance a protein association with MDM2. Concurrently, PRDX1 enhances its association with AR. These protein interaction exchanges result in not only MDM2 protein degradation, but also PRDX1 mediated AR protein stabilization, and subsequent elevation of AR signaling. Blocking PRDX1 by its inhibitor, Conoidin A (CoA), suppresses AR signaling, PCa cell proliferation, and xenograft tumor growth even under androgen-deprived conditions. These tumor-suppressive effects of CoA were further strengthened when in combination with enzalutamide treatment. Together, these studies demonstrate that the TXNDC9-PRDX1 axis plays an important role for ROS to activate AR functions. It provides a proof-of-principle that co-targeting AR and PRDX1 may be more effective to control PCa growth.

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References

  1. 1.

    Fizazi K, Smith MR, Tombal B. Clinical development of darolutamide: a novel androgen receptor antagonist for the treatment of prostate cancer. Clin Genitourin Cancer. 2018;16:332–40.

  2. 2.

    Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002;168:9–12.

  3. 3.

    Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253–61.

  4. 4.

    Sharifi N. Mechanisms of androgen receptor activation in castration-resistant prostate cancer. Endocrinology. 2013;154:4010–7.

  5. 5.

    Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–6.

  6. 6.

    Groner AC, Brown M. Role of steroid receptor and coregulator mutations in hormone-dependent cancers. J Clin Invest. 2017;127:1126–35.

  7. 7.

    Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11:85–95.

  8. 8.

    Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931–47.

  9. 9.

    Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature. 2009;461:109–13.

  10. 10.

    Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14:709–21.

  11. 11.

    Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol. 2002;192:1–15.

  12. 12.

    Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J. 2003;22:5501–10.

  13. 13.

    Shiota M, Yokomizo A, Tada Y, Inokuchi J, Kashiwagi E, Masubuchi D, et al. Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene. 2010;29:237–50.

  14. 14.

    Grad JM, Dai JL, Wu S, Burnstein KL. Multiple androgen response elements and a Myc consensus site in the androgen receptor (AR) coding region are involved in androgen-mediated up-regulation of AR messenger RNA. Mol Endocrinol (Baltim, Md). 1999;13:1896–911.

  15. 15.

    Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharm. 2006;72:1493–505.

  16. 16.

    Zoubeidi A, Zardan A, Beraldi E, Fazli L, Sowery R, Rennie P, et al. Cooperative interactions between androgen receptor (AR) and heat-shock protein 27 facilitate AR transcriptional activity. Cancer Res. 2007;67:10455–65.

  17. 17.

    Yamamoto T, Matsuda T, Junicho A, Kishi H, Saatcioglu F, Muraguchi A. Cross-talk between signal transducer and activator of transcription 3 and estrogen receptor signaling. FEBS Lett. 2000;486:143–8.

  18. 18.

    Jacquot JP, Gelhaye E, Rouhier N, Corbier C, Didierjean C, Aubry A. Thioredoxins and related proteins in photosynthetic organisms: molecular basis for thiol dependent regulation. Biochem Pharm. 2002;64:1065–9.

  19. 19.

    Kakolyris S, Giatromanolaki A, Koukourakis M, Powis G, Souglakos J, Sivridis E, et al. Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer. Clin Cancer Res. 2001;7:3087–91.

  20. 20.

    Grogan TM, Fenoglio-Prieser C, Zeheb R, Bellamy W, Frutiger Y, Vela E, et al. Thioredoxin, a putative oncogene product, is overexpressed in gastric carcinoma and associated with increased proliferation and increased cell survival. Hum Pathol. 2000;31:475–81.

  21. 21.

    Wang L, Song G, Chang X, Tan W, Pan J, Zhu X, et al. The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway. Oncogene. 2015;34:4735–45.

  22. 22.

    Samaranayake GJ, Troccoli CI, Huynh M, Lyles RDZ, Kage K, Win A, et al. Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer. Nat Commun. 2017;8:1204.

  23. 23.

    Gaudet R, Bohm A, Sigler PB. Crystal structure at 2.4 angstroms resolution of the complex of transducin betagamma and its regulator, phosducin. Cell. 1996;87:577–88.

  24. 24.

    Guha P, Kaptan E, Gade P, Kalvakolanu DV, Ahmed H. Tunicamycin induced endoplasmic reticulum stress promotes apoptosis of prostate cancer cells by activating mTORC1. Oncotarget. 2017;8:68191–207.

  25. 25.

    Chen D, Zou J, Zhao Z, Tang X, Deng Z, Jia J, et al. TXNDC9 promotes hepatocellular carcinoma progression by positive regulation of MYC-mediated transcriptional network. Cell Death Dis. 2018;9:1110.

  26. 26.

    Parolia A, Cieslik M, Chu SC, Xiao L, Ouchi T, Zhang Y, et al. Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature. 2019;571:413–8.

  27. 27.

    Xu B, Song B, Lu X, Kim J, Hu M, Zhao JC, et al. Altered chromatin recruitment by FOXA1 mutations promotes androgen independence and prostate cancer progression. Cell Res. 2019. [Epub ahead of print].

  28. 28.

    Rhee SG, Kang SW, Chang TS, Jeong W, Kim K. Peroxiredoxin, a novel family of peroxidases. IUBMB Life. 2001;52:35–41.

  29. 29.

    Kumsta C, Jakob U. Redox-regulated chaperones. Biochemistry. 2009;48:4666–76.

  30. 30.

    Jang HH, Lee KO, Chi YH, Jung BG, Park SK, Park JH, et al. Two enzymes in one; two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function. Cell. 2004;117:625–35.

  31. 31.

    Park SY, Yu X, Ip C, Mohler JL, Bogner PN, Park YM. Peroxiredoxin 1 interacts with androgen receptor and enhances its transactivation. Cancer Res. 2007;67:9294–303.

  32. 32.

    Lin HK, Wang L, Hu YC, Altuwaijri S, Chang C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J. 2002;21:4037–48.

  33. 33.

    Haraldsen JD, Liu G, Botting CH, Walton JG, Storm J, Phalen TJ, et al. Identification of conoidin a as a covalent inhibitor of peroxiredoxin II. Org Biomol Chem. 2009;7:3040–8.

  34. 34.

    Liu G, Botting CH, Evans KM, Walton JA, Xu G, Slawin AM, et al. Optimisation of conoidin A, a peroxiredoxin inhibitor. ChemMedChem. 2010;5:41–45.

  35. 35.

    Best CJ, Gillespie JW, Yi Y, Chandramouli GV, Perlmutter MA, Gathright Y, et al. Molecular alterations in primary prostate cancer after androgen ablation therapy. Clin Cancer Res. 2005;11:6823–34.

  36. 36.

    Shiota M, Yokomizo A, Naito S. Oxidative stress and androgen receptor signaling in the development and progression of castration-resistant prostate cancer. Free Radic Biol Med. 2011;51:1320–8.

  37. 37.

    Tam NN, Gao Y, Leung YK, Ho SM. Androgenic regulation of oxidative stress in the rat prostate: involvement of NAD(P)H oxidases and antioxidant defense machinery during prostatic involution and regrowth. Am J Pathol. 2003;163:2513–22.

  38. 38.

    Nakka M, Agoulnik IU, Weigel NL. Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen-dependent and castration-resistant AR-expressing prostate cancer cells. Int J Biochem Cell Biol. 2013;45:763–72.

  39. 39.

    Harashima K, Akimoto T, Nonaka T, Tsuzuki K, Mitsuhashi N, Nakano T. Heat shock protein 90 (Hsp90) chaperone complex inhibitor, radicicol, potentiated radiation-induced cell killing in a hormone-sensitive prostate cancer cell line through degradation of the androgen receptor. Int J Radiat Biol. 2005;81:63–76.

  40. 40.

    Wang L, Song G, Zhang X, Feng T, Pan J, Chen W, et al. PADI2-mediated citrullination promotes prostate cancer progression. Cancer Res. 2017;77:5755–68.

  41. 41.

    Feng T, Zheng L, Liu F, Xu X, Mao S, Wang X, et al. Growth factor progranulin promotes tumorigenesis of cervical cancer via PI3K/Akt/mTOR signaling pathway. Oncotarget. 2016;7:58381–95.

  42. 42.

    Liu F, Zhang W, Yang F, Feng T, Zhou M, Yu Y, et al. Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling. Sci Rep. 2016;6:21260.

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Funding

This work was supported by the National Key Research And Development Program of China (No. 2018YFC0114703), the National Natural Science Foundation of China (grant nos. 81572544, 81772760, 81472417, 81672554), The Key Research and Development Project of Shandong (grant no. 2016GSF201166), The Shandong Taishan Scholarship (grant no. tsqn20161076).

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Correspondence to Lin Wang or Bo Han.

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