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  • Original Paper
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Maspin sensitizes prostate cancer cells to doxazosin-induced apoptosis

Oncogene volume 24, pages 5375–5383 (2005)Cite this article

Abstract

Maspin is a mammary serine protease inhibitor or serpin with tumor suppressive and antiangiogenic activity that inhibits tumor motility, invasion and metastasis, at least by its actions on cell membrane and extracellular matrix (ECM) proteins. Previous studies documented that the quinazoline-derived α1-adrenoceptor antagonist doxazosin affects the attachment and migration of prostate cancer cells. In this study, we investigated the effect of maspin overexpression on the apoptotic/antiadhesion response of prostate cancer cells to doxazosin. The response of maspin-overexpressing clones of human prostate cancer cells DU-145 to doxazosin was evaluated by determining cell viability, apoptosis and cell proliferation on the basis of the trypan blue exclusion assay/methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, Hoechst staining and caspase-3 activation, and [3H]thymidine incorporation assay. Vascular endothelial growth factor (VEGF), transforming growth factor βRII (TGFβRII), Smad4 (a TGFβ intracellular effector) and bax expression was evaluated at the mRNA and protein level using reverse transcriptase–polymerase chain reaction and Western blotting, respectively. The effect of doxazosin on cell attachment of maspin-expressing prostate cancer cells was evaluated on collagen- and fibronectin-coated plates. Cell migration was assessed using the wounding assay. In response to tumor necrosis factor-related apoptosis-inducing ligand, DU-145-maspin expressing cells undergo apoptosis, via poly(ADP-ribose) polymerasecleavage and caspase-3 activation. DU-145-maspin cells exhibited higher sensitivity to doxazosin and an earlier temporal activation of caspase-3. The number of apoptotic cells detected in response to doxazosin was significantly higher compared to the neo control (P<0.0001). Doxazosin resulted in dramatic downregulation of the 189 isoform of VEGF in maspin transfectants, while a fivefold induction of Smad4 mRNA expression was detected in those cells after 24 h of treatment. Maspin overexpression in prostate cancer cells resulted in an increased ability to attach to ECM-coated plates, and doxazosin treatment considerably antagonized this effect by decreasing the attachment potential to collagen and fibronectin. The present study supports the ability of maspin to enhance the apoptotic threshold of prostate cancer cells to the quinazoline-based α1-adrenoceptor antagonist doxazosin. These findings may have therapeutic significance in the development of antiangiogenic targeting by doxazosin and derivative agents for advanced prostate cancer.

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Abbreviations

BPH:

benign prostatic hyperplasia

ECM:

extracellular matrix

MTT:

methylthiazolyldiphenyl-tetrazolium bromide

PARP:

poly(ADP-ribose) polymerase

TGFβ1:

transforming growth factor β1

TIEG1:

TGFβ1-inducible early gene

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

uPA:

urokinase-type plasminogen activator

VEGF:

vascular endothelial growth factor

References

  • Abraham S, Zhang W, Greenberg N and Zhang M . (2003). J. Urol., 169, 1157–1161.

  • Bare RL and Torti FM . (1998). Cancer Treat. Res., 94, 69–87.

  • Benning CM and Kyprianou N . (2002). Cancer Res., 62, 597–602.

  • Biliran Jr H and Sheng S . (2001). Cancer Res., 61, 676–682.

  • Blacque OE and Worrall DM . (2002). J. Biol. Chem., 277, 10783–10788.

  • Bruckheimer EM and Kyprianou N . (2000). Cell Tissue Res., 301, 153–162.

  • Burchardt M, Burchardt T, Chen MW, Shabsigh A, de la Taille A, Buttyan R and Shabsigh R . (1999). Biol. Reprod., 60, 398–404.

  • Cher ML, Biliran Jr HR, Bhagat S, Meng Y, Che M, Lockett J, Abrams J, Fridman R, Zachareas M and Sheng S . (2003). Proc. Natl. Acad. Sci. USA, 100, 7847–7852.

  • Domann FE, Rice JC, Hendrix MJ and Futscher BW . (2000). Int. J. Cancer, 85, 805–810.

  • Guo Y and Kyprianou N . (1998). Cell Growth Differ., 9, 185–193.

  • Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ and Thun MJ . (2004). CA Cancer J. Clin., 54, 8–29.

  • Jiang N, Meng Y, Zhang S, Mensah-Osman E and Sheng S . (2002). Oncogene, 21, 4089–4098.

  • Keledjian K, Borkowski A, Kim G, Isaacs JT, Jacobs SC and Kyprianou N . (2001). Prostate, 48, 71–78.

  • Keledjian K, Garrison JB and Kyprianou N . (2005). J. Cell. Biochem., 94, 374–388.

  • Keledjian K and Kyprianou N . (2003). J. Urol., 169, 1150–1156.

  • Kyprianou N and Benning CM . (2000). Cancer Res., 60, 4550–4555.

  • Liu J, Yin S, Reddy N, Spencer C and Sheng S . (2004). Cancer Res., 64, 1703–1711.

  • Oades GM, Eaton JD and Kirby RS . (2000). Curr. Urol. Rep., 1, 97–102.

  • Partin JV, Anglin IE and Kyprianou N . (2003). Br. J. Cancer, 88, 1615–1621.

  • Raghavan D, Koczwara B and Javle M . (1997). Eur. J. Cancer, 33, 566–574.

  • Schaefer JS and Zhang M . (2003). Curr. Mol. Med., 3, 653–658.

  • Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ and Sager R . (1996). Proc. Natl. Acad. Sci. USA, 93, 11669–11674.

  • Sheng S, Pemberton PA and Sager R . (1994). J. Biol. Chem., 269, 30988–30993.

  • Shi HY, Zhang W, Liang R, Abraham S, Kittrell FS, Medina D and Zhang M . (2001). Cancer Res., 61, 6945–6951.

  • Sternberg CN . (2003). Eur. J. Cancer, 39, 136–146.

  • Wang J, Sun L, Myeroff L, Wang X, Gentry LE, Yang J, Liang J, Zborowska E, Markowitz S, Willson JK and Brattain MG . (1995). J. Biol. Chem., 270, 22044–22049.

  • Yang G, Timme TL, Park SH, Wu X, Wyllie MG and Thompson TC . (1997). Prostate, 33, 157–163.

  • Zhang M, Volpert O, Shi YH and Bouck N . (2000). Nat. Med., 6, 196–199.

  • Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E and Sager R . (1994). Science, 263, 526–529.

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Acknowledgements

This study was supported by an NIH Grant CA10757-01 (awarded to NK). We wish to thank Dr Shuping Yin (Department of Pathology, Wayne State University School of Medicine) for her skillful technical assistance. We thank Lorie Howard (University of Kentucky) for her expert assistance in the preparation and submission of the manuscript and James Partin (University of Kentucky) for his expertise in the preparation of the figures.

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Authors and Affiliations

  1. Department of Surgery, Division of Urology, University of Kentucky Medical Center, Lexington, KY, USA

    Anastasios Tahmatzopoulos & Natasha Kyprianou

  2. Department of Molecular and Cellular Biochemistry, University of Kentucky Medical Center, Lexington, KY, USA

    Anastasios Tahmatzopoulos & Natasha Kyprianou

  3. Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA

    Shijie Sheng

  4. Department of Pathology, University of Kentucky College of Medicine, Lexington, KY, USA

    Natasha Kyprianou

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  1. Anastasios Tahmatzopoulos
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Correspondence to Natasha Kyprianou.

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Tahmatzopoulos, A., Sheng, S. & Kyprianou, N. Maspin sensitizes prostate cancer cells to doxazosin-induced apoptosis. Oncogene 24, 5375–5383 (2005). https://doi.org/10.1038/sj.onc.1208684

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