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Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells

Oncogene volume 24, pages 3583–3595 (2005)Cite this article

Abstract

Normal human prostatic (NHP) epithelial cells undergo senescence in vitro and in vivo, but little is known about the tissue-specific molecular mechanisms. Here we first characterize young primary NHP cells as CK5+/CK18+ intermediate basal cells that also express several other putative stem/progenitor cell markers including p63, CD44, α2β1, and hTERT. When cultured in serum- and androgen-free medium, NHP cells gradually lose the expression of these markers, slow down in proliferation, and enter senescence. Several pieces of evidence implicate 15-lipoxygenase 2 (15-LOX2), a molecule with a restricted tissue expression and most abundantly expressed in adult human prostate, in the replicative senescence of NHP cells. First, the 15-LOX2 promoter activity and the mRNA and protein levels of 15-LOX2 and its multiple splice variants are upregulated in serially passaged NHP cells, which precede replicative senescence and occur in a cell-autonomous manner. Second, all immortalized prostate epithelial cells and prostate cancer cells do not express 15-LOX2. Third, PCa cells stably transfected with 15-LOX2 or 15-LOX2sv-b, a splice variant that does not possess arachidonate-metabolizing activity, show a passage-related senescence-like phenotype. Fourth, infection of early-passage NHP cells with retroviral vectors encoding 15-LOX2 or 15-LOX2sv-b induces partial cell-cycle arrest and big and flat senescence-like phenotype. Finally, 15-LOX2 protein expression in human prostate correlates with age. Together, these data suggest that 15-LOX2 may represent an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence.

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References

  • Bhatia B, Maldonado CJ, Tang S, Chandra D, Klein RD, Chopra D, Shappell SB, Yang P, Newman RA and Tang DG . (2003). J. Biol. Chem., 278, 25091–25100.

  • Bonkhoff H, Stein U and Remberger K . (1994). Prostate, 24, 42–46.

  • Brash AR, Boeglin WE and Chang MS . (1997). Proc. Natl. Acad. Sci. USA, 94, 6148–6152.

  • Castro P, Giri D, Lamb D and Ittman M . (2003). Prostate, 55, 30–38.

  • Choi J, Shendrik I, Peacocke M, Peehl D, Buttyan R, Ikeguchi EF, Katz AE and Benson MC . (2000). Urology, 56, 160–166.

  • Collins AT, Habib FK, Maitland NJ and Neal DE . (2001). J. Cell Sci., 114, 3865–3872.

  • Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG and Beck JC . (1998). Proc. Natl. Acad. Sci. USA, 95, 10614–10619.

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M and Campisi J . (1995). Proc. Natl. Acad. Sci. USA, 92, 9363–9367.

  • Garraway LA, Lin D, Signoretti S, Waltregny D, Dilks J, Bhattacharya N and Loda M . (2003). Prostate, 55, 206–218.

  • Hanahan D and Weinberg RA . (2000). Cell, 100, 57–70.

  • Huang JT, Welch JS, Ricote M, Binder CJ, Wilson TM, Kelly C, Witztum JL, Funk CD, Conrad D and Glass CK . (1999). Nature, 400, 378–382.

  • Hudson DL, O’Hare M, Watt FM and Masters JRW . (2000). Lab. Invest., 80, 1243–1250.

  • Jarrard DF, Sarkar S, Shi Y, Yeager TR, Magrane G, Kinoshita H, Nassif N, Meisner L, Newton MA, Waldman FM and Reznikoff CA . (1999). Cancer Res., 59, 2957–2964.

  • Kilty I, Alison L and Vickers PJ . (1999). Eur. J. Biochem., 266, 83–93.

  • Kinbara H, Cunha GR, Boutin E, Hayashi N and Kawamura J . (1996). Prostate, 29, 107–116.

  • Kuhn H and Borngraber S . (1999). Adv. Exp. Med. Biol., 447, 5–28.

  • Liu AY, True, LD, LaTray, L, Nelson PS, Ellis WJ, Vessella, RL, Lange, PH, Hood L and van den Engn G . (1997). Proc. Natl. Acad. Sci. USA, 94, 10705–10710.

  • Raff M . (2003). Annu. Rev. Cell Dev. Biol., 19, 1–22.

  • Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ and Collins AT. . (2004). J. Cell Sci. (E-pub June 29).

  • Robinson EJ, Neal DE and Collins AT . (1998). Prostate, 37, 149–160.

  • Ruijter E, van de Kaa C, Miller G, Ruiter D, Debruyne F and Schalken J . (1999). Endocr. Rev., 20, 22–45.

  • Sandhu C, Peehl DM and Singerland J . (2000). Cancer Res., 60, 2616–2622.

  • Schalken JA and van Leenders G . (2003). Urology, 62, 11–20.

  • Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM and Lowe SW . (2002). Cell, 109, 335–346.

  • Schwarze SR, Shi Y, Fu VX, Watson PA and Jarrard DF . (2001). Oncogene, 20, 8184–8192.

  • Shappell SB, Boeglin WE, Olson SJ, Kasper S and Brash AR . (1999). Am. J. Pathol., 155, 235–245.

  • Shou J, Ross S, Koeppen H, de Sauvage FJ and Gao W-Q . (2001). Cancer Res., 61, 7291–7297.

  • Signoretti S, Waltregny D, Dilks J, Isaac B, Lin, D, Garraway L, Yang A, Montironi R, McKeon F and Loda M . (2000). Am. J. Pathol., 157, 1769–1775.

  • Tang DG, Tokumoto YM and Raff MC . (2000). J. Cell Biol., 148, 971–984.

  • Tang DG, Tokumoto YM, Apperly JA, Lloyd AC and Raff MC . (2001). Science, 291, 868–871.

  • Tang S, Bhatia B, Maldonado C, Yang P, Newman RA, Liu J, Chandra D, Traag J, Klein RD, Fischer SM, Chopra D, Shen J, Zhau H, Chung LW-K and Tang DG . (2002). J. Biol. Chem., 277, 16189–16201.

  • Tang S, Bhatia B, Zhou J-J, Maldonado CJ, Chandra D, Kim E, Fischer S, Butler AF, Friedman SL and Tang DG . (2004). Oncogene, 23, 6942–6953.

  • Tran CP, Lin C, Yamashiro J and Reiter RE . (2002). Mol. Cancer Res., 1, 113–121.

  • Untergasser G, Koch, HB, Menssen A and Hermeking H . (2002). Cancer Res., 62, 6255–6262.

  • van Leenders G, Dijkman H, van de Kaa H, Ruiter D and Schalken J . (2000). Lab. Invest., 80, 1251–1258.

  • Wang C, Fu M, A’Mico M, Albanese C, Zhou JN, Brownlee M, Lisanti MP, Chatterjee VKK, Lazar MA and Pestell RG . (2001). Mol. Cell. Biol., 21, 3057–3070.

  • Wright WE and Shay JW . (2001). Curr. Opin. Genet. Dev., 11, 98–103.

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Acknowledgements

We thank D Chopra and J Rhim for providing cells. This work is supported, in part, by NIH grants CA90297 and AG023374, ACS Grant RSG MGO-105961, DOD grant DAMD17-03-1-0137, University of Texas MDACC PCRP and IRG funds, and NIEHS Center Grant P50 ES07784 (all to DGT). RAN was supported by NCI Cancer Center Support grant CA16672 and P01 CA106451.

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Authors and Affiliations

  1. Department of Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park-Research Division, 1808 Park Rd. 1C, Smithville, TX, 78957, USA

    Bobby Bhatia, Shaohua Tang & Dean G Tang

  2. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Peiying Yang & Robert A Newman

  3. Department of Anatomy and Cell Biology, University of Marburg, Marburg, Germany

    Andreas Doll & Gerhard Aumüeller

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  1. Bobby Bhatia
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Correspondence to Dean G Tang.

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Bhatia, B., Tang, S., Yang, P. et al. Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells. Oncogene 24, 3583–3595 (2005). https://doi.org/10.1038/sj.onc.1208406

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