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Adhesion to fibronectin induces p27Kip1 nuclear accumulation through down-regulation of Jab1 and contributes to cell adhesion-mediated drug resistance (CAM-DR) in RPMI 8,226 cells

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Abstract

Mounting evidence has been shown that integrin-mediated cellular adhesion confers resistance to chemotherapy of multiple myeloma. The molecular mechanism underlying cell adhesion-mediated drug resistance (CAM-DR) is, however, poorly understood. In this report, we demonstrated that RPMI 8,226 cells accumulated p27Kip1 in the nucleus when they were adhered to fibronectin (FN). The adhesion-mediated p27Kip1 nuclear recruitment was regulated via the down-regulation of Jab1, a negative regulator of cell cycle. Overexpression of Jab1 reversed the elevated p27Kip1 in the nucleus, which needed phosphorylation of p27Kip1 on Serine 10, whereas inhibition of Jab1 by siRNA further increased the elevated p27Kip1. Furthermore, we found overexpression of Jab1 did not affect 8,226 cells adhesion to FN, but reversed doxorubicin or mitoxantrone-induced CAM-DR phenotype. In conclusion, our data suggest that Jab1 plays an important role in CAM-DR, which depends on pSer10-p27Kip1-mediated subcellular localization of p27Kip1. The understanding of this novel molecular mechanism may prove valuable in designing new therapeutic approaches for CAM-DR in Multiple myeloma.

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Abbreviations

MM:

Multiple myeloma

BM:

Bone marrow

Jab1:

Jun activation domain-binding protein 1

MRD:

Eliminate minimal residual disease

ECM:

Extracellular matrix

FN:

Fibronectin

CAM-DR:

Cell adhesion-mediated drug resistance

CDKI:

Cyclin-dependent kinase inhibitor

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin 62(5):283–298

    Article  PubMed  Google Scholar 

  2. Kyle RA, Rajkumar SV (2008) Multiple myeloma. Blood 111(6):2962–2972

    Article  CAS  PubMed  Google Scholar 

  3. Kyle RA, Rajkumar SV (2004) Multiple myeloma. N Engl J Med 351(18):1860–1873

    Article  CAS  PubMed  Google Scholar 

  4. Anderson KC, Kyle RA, Dalton WS, Landowski T, Shain K, Jove R, Hazlehurst L, Berenson J (2000) Multiple myeloma: new insights and therapeutic approaches. Hematology Am Soc Hematol Educ Program 147–165

  5. Preisler HD, Anderson K, Rai K, Cuttner J, Yates J, DuPre E, Holland JF (1989) The frequency of long-term remission in patients with acute myelogenous leukaemia treated with conventional maintenance chemotherapy: a study of 760 patients with a minimal follow-up time of 6 years. Br J Haematol 71(2):189–194

    Article  CAS  PubMed  Google Scholar 

  6. Preisler HD, Raza A, Larson R, LeBeau M, Browman G, Goldberg J, Grunwald H, Volger R, Verkh L, Singh P et al (1989) Protooncogene expression and the clinical characteristics of acute nonlymphocytic leukemia: a Leukemia Intergroup pilot study. Blood 73(1):255–262

    CAS  PubMed  Google Scholar 

  7. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC (2007) Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 7(8):585–598

    Article  CAS  PubMed  Google Scholar 

  8. Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA, Anderson KC (1996) Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 87(3):1104–1112

    CAS  PubMed  Google Scholar 

  9. Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, Lin BK, Gupta D, Shima Y, Chauhan D, Mitsiades C, Raje N, Richardson P, Anderson KC (2001) Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 98(2):428–435

    Article  CAS  PubMed  Google Scholar 

  10. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS (2000) Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 19(38):4319–4327

    Article  CAS  PubMed  Google Scholar 

  11. Damiano JS, Dalton WS (2000) Integrin-mediated drug resistance in multiple myeloma. Leuk Lymphoma 38(1–2):71–81

    CAS  PubMed  Google Scholar 

  12. Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massague J (1994) Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78(1):59–66

    Article  CAS  PubMed  Google Scholar 

  13. Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78(1):67–74

    Article  CAS  PubMed  Google Scholar 

  14. Coats S, Flanagan WM, Nourse J, Roberts JM (1996) Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. Science 272(5263):877–880

    Article  CAS  PubMed  Google Scholar 

  15. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ (1998) The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396(6707):177–180

    Article  CAS  PubMed  Google Scholar 

  16. Nakayama K (1998) Cip/kip cyclin-dependent kinase inhibitors: brakes of the cell cycle engine during development. Bioessays 20(12):1020–1029

    Article  CAS  PubMed  Google Scholar 

  17. Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13(12):1501–1512

    Article  CAS  PubMed  Google Scholar 

  18. Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR, Roberts JM (1994) Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 372(6506):570–573

    Article  CAS  PubMed  Google Scholar 

  19. Reynisdottir I, Polyak K, Iavarone A, Massague J (1995) Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 9(15):1831–1845

    Article  CAS  PubMed  Google Scholar 

  20. Tsihlias J, Kapusta L, Slingerland J (1999) The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med 50:401–423

    Article  CAS  PubMed  Google Scholar 

  21. Philipp-Staheli J, Payne SR, Kemp CJ (2001) p27(Kip1): regulation and function of a haploinsufficient tumor suppressor and its misregulation in cancer. Exp Cell Res 264(1):148–168

    Article  CAS  PubMed  Google Scholar 

  22. Lwin T, Hazlehurst LA, Dessureault S, Lai R, Bai W, Sotomayor E, Moscinski LC, Dalton WS, Tao J (2007) Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood 110(5):1631–1638

    Article  CAS  PubMed  Google Scholar 

  23. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M (1995) Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269(5224):682–685

    Article  CAS  PubMed  Google Scholar 

  24. Ekholm SV, Reed SI (2000) Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle. Curr Opin Cell Biol 12(6):676–684

    Article  CAS  PubMed  Google Scholar 

  25. Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI (2002) Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J Biol Chem 277(17):14355–14358

    Article  CAS  PubMed  Google Scholar 

  26. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE (1997) Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev 11(11):1464–1478

    Article  CAS  PubMed  Google Scholar 

  27. Vlach J, Hennecke S, Amati B (1997) Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J 16(17):5334–5344

    Article  CAS  PubMed  Google Scholar 

  28. Rodier G, Montagnoli A, Di Marcotullio L, Coulombe P, Draetta GF, Pagano M, Meloche S (2001) p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20(23):6672–6682

    Article  CAS  PubMed  Google Scholar 

  29. Tomoda K, Kubota Y, Kato J (1999) Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398(6723):160–165

    Article  CAS  PubMed  Google Scholar 

  30. Tomoda K, Kubota Y, Arata Y, Mori S, Maeda M, Tanaka T, Yoshida M, Yoneda-Kato N, Kato JY (2002) The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex. J Biol Chem 277(3):2302–2310

    Article  CAS  PubMed  Google Scholar 

  31. Shen A, Wang Y, Zhao Y, Zou L, Sun L, Cheng C (2009) Expression of CRM1 in human gliomas and its significance in p27 expression and clinical prognosis. Neurosurgery 65(1):153–159

    Article  PubMed  Google Scholar 

  32. Sui L, Dong Y, Ohno M, Watanabe Y, Sugimoto K, Tai Y, Tokuda M (2001) Jab1 expression is associated with inverse expression of p27(kip1) and poor prognosis in epithelial ovarian tumors. Clin Cancer Res 7(12):4130–4135

    CAS  PubMed  Google Scholar 

  33. Tsuchida R, Miyauchi J, Shen L, Takagi M, Tsunematsu Y, Saeki M, Honna T, Yamada S, Teraoka H, Kato JY, Mizutani S (2002) Expression of cyclin-dependent kinase inhibitor p27/Kip1 and AP-1 coactivator p38/Jab1 correlates with differentiation of embryonal rhabdomyosarcoma. Jpn J Cancer Res 93(9):1000–1006

    Article  CAS  PubMed  Google Scholar 

  34. Esteva FJ, Sahin AA, Rassidakis GZ, Yuan LX, Smith TL, Yang Y, Gilcrease MZ, Cristofanilli M, Nahta R, Pusztai L, Claret FX (2003) Jun activation domain binding protein 1 expression is associated with low p27(Kip1)levels in node-negative breast cancer. Clin Cancer Res 9(15):5652–5659

    CAS  PubMed  Google Scholar 

  35. Ito Y, Yoshida H, Matsuzuka F, Matsuura N, Nakamura Y, Nakamine H, Kakudo K, Kuma K, Miyauchi A (2003) Jun activation domain-binding protein 1 expression in malignant lymphoma of the thyroid: its linkage to degree of malignancy and p27 expression. Anticancer Res 23(5b):4121–4125

    CAS  PubMed  Google Scholar 

  36. Kouvaraki MA, Rassidakis GZ, Tian L, Kumar R, Kittas C, Claret FX (2003) Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27(Kip1). Cancer Res 63(11):2977–2981

    CAS  PubMed  Google Scholar 

  37. Shintani S, Li C, Mihara M, Hino S, Nakashiro K, Hamakawa H (2003) Skp2 and Jab1 expression are associated with inverse expression of p27(KIP1) and poor prognosis in oral squamous cell carcinomas. Oncology 65(4):355–362

    Article  CAS  PubMed  Google Scholar 

  38. Fukumoto A, Ikeda N, Sho M, Tomoda K, Kanehiro H, Hisanaga M, Tsurui Y, Tsutsumi M, Kato JY, Nakajima Y (2004) Prognostic significance of localized p27Kip1 and potential role of Jab1/CSN5 in pancreatic cancer. Oncol Rep 11(2):277–284

    CAS  PubMed  Google Scholar 

  39. Ivan D, Diwan AH, Esteva FJ, Prieto VG (2004) Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions. Mod Pathol 17(7):811–818

    Article  CAS  PubMed  Google Scholar 

  40. Ito Y, Miyoshi E, Uda E, Yoshida H, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Matsuura N, Kakudo K, Kuma K, Miyauchi A (2003) 14-3-3 sigma possibly plays a constitutive role in papillary carcinoma, but not in follicular tumor of the thyroid. Cancer Lett 196(1):87–91

    Article  CAS  PubMed  Google Scholar 

  41. Rassidakis GZ, Claret FX, Lai R, Zhang Q, Sarris AH, McDonnell TJ, Medeiros LJ (2003) Expression of p27(Kip1) and c-Jun activation binding protein 1 are inversely correlated in systemic anaplastic large cell lymphoma. Clin Cancer Res 9(3):1121–1128

    CAS  PubMed  Google Scholar 

  42. Chopra S, Fernandez De Mattos S, Lam EW, Mann DJ (2002) Jab1 co-activation of c-Jun is abrogated by the serine 10-phosphorylated form of p27Kip1. J Biol Chem 277(36):32413–32416

    Article  CAS  PubMed  Google Scholar 

  43. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS (1999) Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93(5):1658–1667

    CAS  PubMed  Google Scholar 

  44. Hang Q, Fei M, Hou S, Ni Q, Lu C, Zhang G, Gong P, Guan C, Huang X, He S (2012) Expression of Spy1 protein in human non-Hodgkin’s lymphomas is correlated with phosphorylation of p27 Kip1 on Thr187 and cell proliferation. Med Oncol 29(5):3504–3514

    Article  CAS  PubMed  Google Scholar 

  45. Bell MP, Huntoon CJ, Graham D, McKean DJ (2001) The analysis of costimulatory receptor signaling cascades in normal T lymphocytes using in vitro gene transfer and reporter gene analysis. Nat Med 7(10):1155–1158

    Article  CAS  PubMed  Google Scholar 

  46. Hazlehurst LA, Dalton WS (2001) Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. Cancer Metastasis Rev 20(1–2):43–50

    Article  CAS  PubMed  Google Scholar 

  47. Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6(5):369–381

    Article  CAS  PubMed  Google Scholar 

  48. Nimmanapalli R, Gerbino E, Dalton WS, Gandhi V, Alsina M (2008) HSP70 inhibition reverses cell adhesion mediated and acquired drug resistance in multiple myeloma. Br J Haematol 142(4):551–561

    Article  CAS  PubMed  Google Scholar 

  49. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, Akiyama T, Kuroda H, Kawano Y, Kobune M, Kato J, Hirayama Y, Sakamaki S, Kohda K, Miyake K, Niitsu Y (2003) Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 9(9):1158–1165

    Article  CAS  PubMed  Google Scholar 

  50. Chamovitz DA, Segal D (2001) JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep 2(2):96–101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Schwechheimer C, Deng XW (2001) COP9 signalosome revisited: a novel mediator of protein degradation. Trends Cell Biol 11(10):420–426

    Article  CAS  PubMed  Google Scholar 

  52. Xirodimas DP, Saville MK, Bourdon JC, Hay RT, Lane DP (2004) Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 118(1):83–97

    Article  CAS  PubMed  Google Scholar 

  53. Ishida N, Kitagawa M, Hatakeyama S, Nakayama K (2000) Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability. J Biol Chem 275(33):25146–25154

    Article  CAS  PubMed  Google Scholar 

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Conflict of interest

All the authors declare no conflict of interest.

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Authors and Affiliations

  1. Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China

    Min Fei & Changgeng Ruan

  2. Institute of Medical Biotechnology, Soochow University, Suzhou, Jiangsu, China

    Min Fei

  3. Department of Immunology, Medical College of Nantong University, Nantong, 226001, Jiangsu, China

    Qinglei Hang

  4. Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi, Japan

    Qinglei Hang

  5. Department of Emergency, Subei People’s Hospital, Clinical Medical College of Yangzhou University, Nantong West Road 98, Yangzhou, 225001, China

    Sicong Hou

  6. Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China

    Songbin He

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  1. Min Fei
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  2. Qinglei Hang
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  3. Sicong Hou
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Correspondence to Changgeng Ruan.

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The authors M. Fei and Q. Hang contributed equally to this work.

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Fei, M., Hang, Q., Hou, S. et al. Adhesion to fibronectin induces p27Kip1 nuclear accumulation through down-regulation of Jab1 and contributes to cell adhesion-mediated drug resistance (CAM-DR) in RPMI 8,226 cells. Mol Cell Biochem 386, 177–187 (2014). https://doi.org/10.1007/s11010-013-1856-7

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  • DOI: https://doi.org/10.1007/s11010-013-1856-7

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