Advertisement

Tumor Biology

, Volume 36, Issue 8, pp 6383–6390 | Cite as

Leucine-rich repeat-containing protein 59 mediates nuclear import of cancerous inhibitor of PP2A in prostate cancer cells

  • Rajash Pallai
  • Aishwarya Bhaskar
  • Natalie Barnett-Bernodat
  • Christina Gallo-Ebert
  • Michelle Pusey
  • Joseph T. NickelsJr.
  • Lyndi M. Rice
Research Article

Abstract

Using yeast two-hybrid analysis, we identified several novel protein interactions for the oncoprotein Cancerous Inhibitor of PP2A (CIP2A) and confirmed a subset of these interactions in human cancer cell lines. Analysis of the interaction in prostate carcinoma cells between CIP2A and leucine-rich repeat-containing protein 59 (LRRC59) suggests that CIP2A is translocated into the nucleus at G2/M through its association with LRRC59. Recent work by others has demonstrated that nuclear CIP2A disrupts mitotic checkpoints, which promotes deregulation of the cell cycle and increases cancerous phenotypes. Thus, we provide a novel therapeutic mechanism for inhibiting CIP2A function in cancerous cells via targeting the CIP2A-LRRC59 interaction.

Keywords

CIP2A LRRC59 PP2A Prostate cancer Biomarker 

Notes

Acknowledgments

We would like to express our deepest gratitude to Dr. Eli Mordechai and Genesis Biotechnology Group, LLC for the financial support of this work. We also wish to thank Drs. Martin Adelson, Jason Trama, Igor Pechik, and Maria Webb for intellectual contributions to this work and Diana Savoly, Amy Werda, Jamie Francisco for their aid in these studies.

Conflicts of interest

All authors are employed by Genesis Biotechnology Group, LLC (GBG), and the work described was funded by GBG.

Supplementary material

13277_2015_3326_MOESM1_ESM.doc (233 kb)
ESM 1 (DOC 233 kb)

References

  1. 1.
    Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2a regulatory subunits and cancer. Biochim Biophys Acta. 2009;1795:1–15.PubMedGoogle Scholar
  2. 2.
    Mumby M. Pp2a: unveiling a reluctant tumor suppressor. Cell. 2007;130:21–4.CrossRefPubMedGoogle Scholar
  3. 3.
    Westermarck J, Hahn WC. Multiple pathways regulated by the tumor suppressor pp2a in transformation. Trends Mol Med. 2008;14:152–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Fey D, Croucher DR, Kolch W, Kholodenko BN. Crosstalk and signaling switches in mitogen-activated protein kinase cascades. Front Physiol. 2012;3:355.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Jackson JB, Pallas DC. Circumventing cellular control of pp2a by methylation promotes transformation in an akt-dependent manner. Neoplasia. 2012;14:585–99.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Letourneux C, Rocher G, Porteu F. B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk. EMBO J. 2006;25:727–38.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rodgers JT, Vogel RO, Puigserver P. Clk2 and b56beta mediate insulin-regulated assembly of the pp2a phosphatase holoenzyme complex on akt. Mol Cell. 2011;41:471–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Jayadeva G, Kurimchak A, Garriga J, Sotillo E, Davis AJ, Haines DS, et al. B55alpha pp2a holoenzymes modulate the phosphorylation status of the retinoblastoma-related protein p107 and its activation. J Biol Chem. 2010;285:29863–73.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Nobumori Y, Shouse GP, Fan L, Liu X. Heat repeat 1 motif is required for b56gamma-containing protein phosphatase 2a (b56gamma-pp2a) holoenzyme assembly and tumor-suppressive function. J Biol Chem. 2012;287:11030–6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Shouse GP, Nobumori Y, Panowicz MJ, Liu X. Atm-mediated phosphorylation activates the tumor-suppressive function of b56gamma-pp2a. Oncogene. 2011;30:3755–65.CrossRefPubMedGoogle Scholar
  11. 11.
    Sablina AA, Hector M, Colpaert N, Hahn WC. Identification of pp2a complexes and pathways involved in cell transformation. Cancer Res. 2010;70:10474–84.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Agarwal A, MacKenzie RJ, Pippa R, Eide CA, Oddo J, Tyner JW, et al. Antagonism of set using op449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia. Clin Cancer Res. 2014;20:2092–103.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cristobal I, Manso R, Rincon R, Carames C, Senin C, Borrero A, et al. Pp2a inhibition is a common event in colorectal cancer and its restoration using fty720 shows promising therapeutic potential. Mol Cancer Ther. 2014;13:938–47.CrossRefPubMedGoogle Scholar
  14. 14.
    Janghorban M, Farrell AS, Allen-Petersen BL, Pelz C, Daniel CJ, Oddo J, et al. Targeting c-myc by antagonizing pp2a inhibitors in breast cancer. Proc Natl Acad Sci U S A. 2014;111:9157–62.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Puustinen P, Junttila MR, Vanhatupa S, Sablina AA, Hector ME, Teittinen K, et al. Pme-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2a-mediated inactivation in human malignant glioma. Cancer Res. 2009;69:2870–7.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wandzioch E, Pusey M, Werda A, Bail S, Bhaskar A, Nestor M, et al. Pme-1 modulates protein phosphatase 2a activity to promote the malignant phenotype of endometrial cancer cells. Cancer Res. 2014;74:4295–305.CrossRefPubMedGoogle Scholar
  17. 17.
    Junttila MR, Puustinen P, Niemela M, Ahola R, Arnold H, Bottzauw T, et al. Cip2a inhibits pp2a in human malignancies. Cell. 2007;130:51–62.CrossRefPubMedGoogle Scholar
  18. 18.
    Vaarala MH, Vaisanen MR, Ristimaki A. Cip2a expression is increased in prostate cancer. J Exp Clin Cancer Res. 2010;29:136.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Bockelman C, Lassus H, Hemmes A, Leminen A, Westermarck J, Haglund C, et al. Prognostic role of cip2a expression in serous ovarian cancer. Br J Cancer. 2011;105:989–95.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Teng HW, Yang SH, Lin JK, Chen WS, Lin TC, Jiang JK, et al. Cip2a is a predictor of poor prognosis in colon cancer. J Gastrointest Surg. 2012;16:1037–47.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang L, Gu F, Ma N, Zhang L, Bian JM, Cao HY. Cip2a expression is associated with altered expression of epithelial-mesenchymal transition markers and predictive of poor prognosis in pancreatic ductal adenocarcinoma. Tumour Biol. 2013;34:2309–13.CrossRefPubMedGoogle Scholar
  22. 22.
    Yu HC, Hou DR, Liu CY, Lin CS, Shiau CW, Cheng AL, et al. Cancerous inhibitor of protein phosphatase 2a mediates bortezomib-induced autophagy in hepatocellular carcinoma independent of proteasome. PLoS One. 2013;8:e55705.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Yu HC, Hung MH, Chen YL, Chu PY, Wang CY, Chao TT, et al. Erlotinib derivative inhibits hepatocellular carcinoma by targeting cip2a to reactivate protein phosphatase 2a. Cell Death Dis. 2014;5:e1359.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Huang J, Jia J, Tong Q, Liu J, Qiu J, Sun R, et al. Knockdown of cancerous inhibitor of protein phosphatase 2a may sensitize metastatic castration-resistant prostate cancer cells to cabazitaxel chemotherapy. Tumor Biol. 2014.Google Scholar
  25. 25.
    De P, Carlson J, Leyland-Jones B, Dey N. Oncogenic nexus of cancerous inhibitor of protein phosphatase 2a (cip2a): an oncoprotein with many hands. Oncotarget. 2014;5:4581–602.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Junttila MR, Westermarck J. Mechanisms of myc stabilization in human malignancies. Cell Cycle. 2008;7:592–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Jeong AL, Lee S, Park JS, Han S, Jang CY, Lim JS, et al. Cancerous inhibitor of protein phosphatase 2a (cip2a) is involved in centrosome separation through the regulation of nima-related kinase 2 (nek2) activity. J Biol Chem. 2014;289:28–40.CrossRefPubMedGoogle Scholar
  28. 28.
    Kim JS, Kim EJ, Oh JS, Park IC, Hwang SG. Cip2a modulates cell-cycle progression in human cancer cells by regulating the stability and activity of plk1. Cancer Res. 2013;73:6667–78.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhen Y, Sorensen V, Skjerpen CS, Haugsten EM, Jin Y, Walchli S, et al. Nuclear import of exogenous fgf1 requires the er-protein lrrc59 and the importins kpnalpha1 and kpnbeta1. Traffic. 2012;13:650–64.CrossRefPubMedGoogle Scholar
  30. 30.
    Pallai R, Bhaskar A, Sodi V, Rice LM. Ets1 and elk1 transcription factors regulate cancerous inhibitor of protein phosphatase 2a expression in cervical and endometrial carcinoma cells. Transcription. 2012;3:323–35.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Terp MG, Lund RR, Jensen ON, Leth-Larsen R, Ditzel HJ. Identification of markers associated with highly aggressive metastatic phenotypes using quantitative comparative proteomics. Cancer Genomics Proteomics. 2012;9:265–73.PubMedGoogle Scholar
  32. 32.
    Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, et al. Cip2a is associated with human breast cancer aggressivity. Clin Cancer Res. 2009;15:5092–100.CrossRefPubMedGoogle Scholar
  33. 33.
    Yu G, Liu G, Dong J, Jin Y. Clinical implications of cip2a protein expression in breast cancer. Med Oncol. 2013;30:524.CrossRefPubMedGoogle Scholar
  34. 34.
    Yu YP, Ding Y, Chen Z, Liu S, Michalopoulos A, Chen R, et al. Novel fusion transcripts associate with progressive prostate cancer. Am J Pathol. 2014;184:2840–9.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fang Y, Li Z, Wang X, Zhang S. Cip2a is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. Tumour Biol. 2012;33:2299–306.CrossRefPubMedGoogle Scholar
  36. 36.
    Huang LP, Savoly D, Sidi AA, Adelson ME, Mordechai E, Trama JP. Cip2a protein expression in high-grade, high-stage bladder cancer. Cancer Med. 2012;1:76–81.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Katz J, Jakymiw A, Ducksworth MK, Stewart CM, Bhattacharyya I, Cha S, et al. Cip2a expression and localization in oral carcinoma and dysplasia. Cancer Biol Ther. 2010;10:694–9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lilja L, Haapasaari KM, Bloigu R, Salonen T, Ristimaki A, Turpeenniemi-Hujanen T, et al. Increased expression of cip2a in aggressive subtypes of b-cell lymphoma. Histopathology. 2013;63:438–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Rantanen T, Kauttu T, Akerla J, Honkanen T, Krogerus L, Salo J, et al. Cip2a expression and prognostic role in patients with esophageal adenocarcinoma. Med Oncol. 2013;30:684.CrossRefPubMedGoogle Scholar
  40. 40.
    Wang J, Huang T, Sun J, Yu Y, Liu Z, Li W, et al. Cip2a is overexpressed and involved in the pathogenesis of chronic myelocytic leukemia by interacting with breakpoint cluster region-abelson leukemia virus. Med Oncol. 2014;31:112.CrossRefPubMedGoogle Scholar
  41. 41.
    Bockelman C, Koskensalo S, Hagstrom J, Lundin M, Ristimaki A, Haglund C. Cip2a overexpression is associated with c-myc expression in colorectal cancer. Cancer Biol Ther. 2012;13:289–95.CrossRefPubMedGoogle Scholar
  42. 42.
    Khanna A, Kauko O, Bockelman C, Laine A, Schreck I, Partanen JI, et al. Chk1 targeting reactivates pp2a tumor suppressor activity in cancer cells. Cancer Res. 2013;73:6757–69.CrossRefPubMedGoogle Scholar
  43. 43.
    Khanna A, Okkeri J, Bilgen T, Tiirikka T, Vihinen M, Visakorpi T, et al. Ets1 mediates mek1/2-dependent overexpression of cancerous inhibitor of protein phosphatase 2a (cip2a) in human cancer cells. PLoS One. 2011;6:e17979.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lin YC, Chen KC, Chen CC, Cheng AL, Chen KF. Cip2a-mediated akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral Oncol. 2012;48:585–93.CrossRefPubMedGoogle Scholar
  45. 45.
    Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR, et al. Cip2a mediates effects of bortezomib on phospho-akt and apoptosis in hepatocellular carcinoma cells. Oncogene. 2010;29:6257–66.CrossRefPubMedGoogle Scholar
  46. 46.
    Lee J, Jeong H, Park EJ, Hwang JW, Huang B, Bae EK, et al. Cip2a facilitates apoptotic resistance of fibroblast-like synoviocytes in rheumatoid arthritis independent of c-myc expression. Rheumatol Int. 2013;33:2241–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Tseng LM, Liu CY, Chang KC, Chu PY, Shiau CW, Chen KF. Cip2a is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res. 2012;14:R68.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Yu HC, Chen HJ, Chang YL, Liu CY, Shiau CW, Cheng AL, et al. Inhibition of cip2a determines erlotinib-induced apoptosis in hepatocellular carcinoma. Biochem Pharmacol. 2013;85:356–66.CrossRefPubMedGoogle Scholar
  49. 49.
    Florenes VA, Emilsen E, Dong HP, Forsund M, Holm R, Slipicevic A. Cellular localization of cip2a determines its prognostic impact in superficial spreading and nodular melanoma. Cancer Med. 2015.Google Scholar
  50. 50.
    Buchwald P. Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life. 2010;62:724–31.CrossRefPubMedGoogle Scholar
  51. 51.
    Fletcher S, Hamilton AD. Protein-protein interaction inhibitors: small molecules from screening techniques. Curr Top Med Chem. 2007;7:922–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Pallai R, Bhaskar A, Barnett-Bernodat N, Gallo-Ebert C, Nickels JT, Rice LM. Cancerous inhibitor of protein phosphatase 2A promotes premature chromosome segregation and aneuploidy in prostate cancer cells through association with shugoshin. Tumor Biol. 2015. doi: 10.1007/s13277-015-3284-7.
  53. 53.
    Ventela S, Come C, Makela JA, Hobbs RM, Mannermaa L, Kallajoki M, et al. Cip2a promotes proliferation of spermatogonial progenitor cells and spermatogenesis in mice. PLoS One. 2012;7:e33209.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Rajash Pallai
    • 1
  • Aishwarya Bhaskar
    • 1
  • Natalie Barnett-Bernodat
    • 2
    • 3
  • Christina Gallo-Ebert
    • 2
  • Michelle Pusey
    • 1
  • Joseph T. NickelsJr.
    • 2
  • Lyndi M. Rice
    • 1
  1. 1.Oncoveda, Cancer Signaling and Cell Cycle Team, Medical Diagnostic Laboratories, LLCGenesis Biotechnology GroupHamiltonUSA
  2. 2.Institute of Metabolic DisordersGenesis Biotechnology GroupHamiltonUSA
  3. 3.Femeris, Medical Diagnostic Laboratories, LLCGenesis Biotechnology GroupHamiltonUSA

Personalised recommendations