Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Galectin-3 regulates p21 stability in human prostate cancer cells

Abstract

Galectin-3 (Gal-3) is a multifunctional protein involved in cancer through regulation of cell adhesion, cell growth, apoptosis and metastasis, while p21 (Cip1/WAF1) is a negative regulator of the cell cycle, involved in apoptosis, transcription, DNA repair and metastasis. The results presented here demonstrate for the first time that the level of Gal-3 protein is associated with the level of p21 protein expression in human prostate cancer cells and the effects of Gal-3 on cell growth and apoptosis were reversed by modulating p21 expression level. Furthermore, Gal-3 regulates p21 expression at the post-translational level by stabilizing p21 protein via the carbohydrate-recognition domain. This is the first report suggesting a molecular function not yet described for Gal-3 as the regulator of p21 protein stability. This study provides a unique insight into the relationship of these two molecules during prostate cancer progression, and may provide a novel therapeutic target.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Barondes SH, Cooper DN, Gitt MA, Leffler H . Galectins. Structure and function of a large family of animal lectins. J Biol Chem 1994; 269: 20807–20810.

    CAS  PubMed  Google Scholar 

  2. Feilchenfeldt J, Totsch M, Sheu SY, Robert J, Spiliopoulos A, Frilling A et al. Expression of galectin-3 in normal and malignant thyroid tissue by quantitative PCR and immunohistochemistry. Mod Pathol 2003; 16: 1117–1123.

    Article  PubMed  Google Scholar 

  3. Puglisi F, Minisini AM, Barbone F, Intersimone D, Aprile G, Puppin C et al. Galectin-3 expression in non-small cell lung carcinoma. Cancer Lett 2004; 212: 233–239.

    Article  CAS  PubMed  Google Scholar 

  4. Idikio H . Galectin-3 expression in human breast carcinoma: correlation with cancer histologic grade. Int J Oncol 1998; 12: 1287–1290.

    CAS  PubMed  Google Scholar 

  5. Merseburger AS, Kramer MW, Hennenlotter J, Simon P, Knapp J, Hartmann JT et al. Involvement of decreased Galectin-3 expression in the pathogenesis and progression of prostate cancer. Prostate 2008; 68: 72–77.

    Article  PubMed  Google Scholar 

  6. Wang Y, Nangia-Makker P, Tait L, Balan V, Hogan V, Pienta KJ et al. Regulation of prostate cancer progression by galectin-3. Am J Pathol 2009; 174: 1515–1523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lin HM, Moon BK, Yu F, Kim HR . Galectin-3 mediates genistein-induced G(2)/M arrest and inhibits apoptosis. Carcinogenesis 2000; 21: 1941–1945.

    Article  CAS  PubMed  Google Scholar 

  8. Yang LP, Jiang S, Liu JQ, Miao XY, Yang ZL . Association of immunostaining of galectin-3 and sambucus nigra agglutinin with invasion, metastasis and poor progression of gallbladder adenocarcinoma. Hepatogastroenterology (e-pub ahead of print 12 April 2012; doi:10.5754/hge12129).

  9. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805–816.

    Article  CAS  PubMed  Google Scholar 

  10. Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA . Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. Proc Natl Acad Sci USA 1999; 96: 1002–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Garner E, Raj K . Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle 2008; 7: 277–282.

    Article  CAS  PubMed  Google Scholar 

  12. Coqueret O . New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 2003; 13: 65–70.

    Article  CAS  PubMed  Google Scholar 

  13. Podust VN, Podust LM, Goubin F, Ducommun B, Hubscher U . Mechanism of inhibition of proliferating cell nuclear antigen-dependent DNA synthesis by the cyclin-dependent kinase inhibitor p21. Biochemistry 1995; 34: 8869–8875.

    Article  CAS  PubMed  Google Scholar 

  14. Streetly MJ, Maharaj L, Joel S, Schey SA, Gribben JG, Cotter FE . GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood 2010; 115: 3939–3948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995; 376: 37–43.

    Article  CAS  PubMed  Google Scholar 

  16. Califice S, Castronovo V, Van Den Brule F . Galectin-3 and cancer (Review). Int J Oncol 2004; 25: 983–992.

    CAS  PubMed  Google Scholar 

  17. Bartolazzi A, D'Alessandria C, Parisella MG, Signore A, Del Prete F, Lavra L et al. Thyroid cancer imaging in vivo by targeting the anti-apoptotic molecule galectin-3. PLoS One 2008; 3: e3768.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Iacovazzi PA, Notarnicola M, Caruso MG, Guerra V, Frisullo S, Altomare DF . Serum levels of galectin-3 and its ligand 90k/mac-2bp in colorectal cancer patients. Immunopharmacol Immunotoxicol 2010; 32: 160–164.

    Article  CAS  PubMed  Google Scholar 

  19. Nangia-Makker P, Sarvis R, Visscher DW, Bailey-Penrod J, Raz A, Sarkar FH . Galectin-3 and L1 retrotransposons in human breast carcinomas. Breast Cancer Res Treat 1998; 49: 171–183.

    Article  CAS  PubMed  Google Scholar 

  20. Brustmann H . Epidermal growth factor receptor expression in serous ovarian carcinoma: an immunohistochemical study with galectin-3 and cyclin D1 and outcome. Int J Gynecol Pathol 2008; 27: 380–389.

    Article  PubMed  Google Scholar 

  21. Ellerhorst JA, Stephens LC, Nguyen T, Xu XC . Effects of galectin-3 expression on growth and tumorigenicity of the prostate cancer cell line LNCaP. Prostate 2002; 50: 64–70.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Nangia-Makker P, Balan V, Hogan V, Raz A . Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death Dis 2010; 1: e101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Abbas T, Dutta A . p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 2009; 9: 400–414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Suzuki A, Tsutomi Y, Miura M, Akahane K . Caspase 3 inactivation to suppress Fas-mediated apoptosis: identification of binding domain with p21 and ILP and inactivation machinery by p21. Oncogene 1999; 18: 1239–1244.

    Article  CAS  PubMed  Google Scholar 

  25. Le HV, Minn AJ, Massague J . Cyclin-dependent kinase inhibitors uncouple cell cycle progression from mitochondrial apoptotic functions in DNA-damaged cancer cells. J Biol Chem 2005; 280: 32018–32025.

    Article  CAS  PubMed  Google Scholar 

  26. Stivala LA, Cazzalini O, Prosperi E . The cyclin-dependent kinase inhibitor p21CDKN1A as a target of anti-cancer drugs. Curr Cancer Drug Targets 2012; 12: 85–96.

    Article  CAS  PubMed  Google Scholar 

  27. Caffo O, Doglioni C, Veronese S, Bonzanini M, Marchetti A, Buttitta F et al. Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up. Clin Cancer Res 1996; 2: 1591–1599.

    CAS  PubMed  Google Scholar 

  28. Anttila MA, Kosma VM, Hongxiu J, Puolakka J, Juhola M, Saarikoski S et al. p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. Br J Cancer 1999; 79: 1870–1878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ogawa M, Onoda N, Maeda K, Kato Y, Nakata B, Kang SM et al. A combination analysis of p53 and p21 in gastric carcinoma as a strong indicator for prognosis. Int J Mol Med 2001; 7: 479–483.

    CAS  PubMed  Google Scholar 

  30. Baretton GB, Klenk U, Diebold J, Schmeller N, Lohrs U . Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy: prognostic significance of p21/WAF1/CIP1 expression. Br J Cancer 1999; 80: 546–555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim HR, Lin HM, Biliran H, Raz A . Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. Cancer Res 1999; 59: 4148–4154.

    CAS  PubMed  Google Scholar 

  32. Waldman T, Lengauer C, Kinzler KW, Vogelstein B . Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 1996; 381: 713–716.

    Article  CAS  PubMed  Google Scholar 

  33. Kraljevic Pavelic S, Cacev T, Kralj M . A dual role of p21waf1/cip1 gene in apoptosis of HEp-2 treated with cisplatin or methotrexate. Cancer Gene Ther 2008; 15: 576–590.

    Article  CAS  PubMed  Google Scholar 

  34. Blagosklonny MV . Are p27 and p21 cytoplasmic oncoproteins? Cell Cycle 2002; 1: 391–393.

    Article  CAS  PubMed  Google Scholar 

  35. Lee EW, Lee MS, Camus S, Ghim J, Yang MR, Oh W et al. Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis. Embo J 2009; 28: 2100–2113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gan L, Wang J, Xu H, Yang X . Resistance to docetaxel-induced apoptosis in prostate cancer cells by p38/p53/p21 signaling. Prostate 2011; 71: 1158–1166.

    Article  CAS  PubMed  Google Scholar 

  37. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817–825.

    Article  CAS  PubMed  Google Scholar 

  38. Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A et al. p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science 1995; 267: 1024–1027.

    Article  CAS  PubMed  Google Scholar 

  39. Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A . Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 2003; 278: 25752–25757.

    Article  CAS  PubMed  Google Scholar 

  40. Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM, Clurman BE . Proteasomal turnover of p21Cip1 does not require p21Cip1 ubiquitination. Mol Cell 2000; 5: 403–410.

    Article  CAS  PubMed  Google Scholar 

  41. Amador V, Ge S, Santamaria PG, Guardavaccaro D, Pagano M . APC/C(Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase. Mol Cell 2007; 27: 462–473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim Y, Starostina NG, Kipreos ET . The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev 2008; 22: 2507–2519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ . A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome. EMBO J 2001; 20: 2367–2375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gong J, Ammanamanchi S, Ko TC, Brattain MG . Transforming growth factor beta 1 increases the stability of p21/WAF1/CIP1 protein and inhibits CDK2 kinase activity in human colon carcinoma FET cells. Cancer Res 2003; 63: 3340–3346.

    CAS  PubMed  Google Scholar 

  45. Beck SE, Jung BH, Del Rosario E, Gomez J, Carethers JM . BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK. Cell Signal 2007; 19: 1465–1472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Balan V, Nangia-Makker P, Kho DH, Wang Y, Raz A . Tyrosine-phosphorylated galectin-3 protein is resistant to prostate-specific antigen (PSA) cleavage. J Biol Chem 2012; 287: 5192–5198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Roy A, Kucukural A, Zhang Y . I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 2010; 5: 725–738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Seetharaman J, Kanigsberg A, Slaaby R, Leffler H, Barondes SH, Rini JM . X-ray crystal structure of the human galectin-3 carbohydrate recognition domain at 2.1-A resolution. J Biol Chem 1998; 273: 13047–13052.

    Article  CAS  PubMed  Google Scholar 

  49. Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ . PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 2005; 33: W363–W367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mashiach E, Schneidman-Duhovny D, Andrusier N, Nussinov R, Wolfson HJ . FireDock: a web server for fast interaction refinement in molecular docking. Nucleic Acids Res 2008; 36: W229–W232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr Reuben Lotan for providing Gal-3-transfected LNCaP clones. This study was supported by the National Institutes of Health grant R37CA46120-19 (A Raz) and the American Cancer Society grant 11-053-01-IRG (V Balan).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to P Nangia-Makker or A Raz.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Y., Balan, V., Kho, D. et al. Galectin-3 regulates p21 stability in human prostate cancer cells. Oncogene 32, 5058–5065 (2013). https://doi.org/10.1038/onc.2012.528

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.528

Keywords

This article is cited by

Search

Quick links