Home LiteratureArticle Details
PMID: 18441325 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells.

The Journal of biological chemistry ·Vol. 283 ·No. 25 ·2008-06-20 ·Pages 17635-51

Bourguignon LY, Peyrollier K, Xia W, Gilad E

Abstract

Hyaluronan (HA) is a major glycosaminoglycan in the extracellular matrix whose expression is tightly linked to multidrug resistance and tumor progression. In this study we investigated HA-induced interaction between CD44 (a HA receptor) and Nanog (an embryonic stem cell transcription factor) in both human breast tumor cells (MCF-7 cells) and human ovarian tumor cells (SK-OV-3.ipl cells). Using a specific primer pair to amplify Nanog by reverse transcriptase-PCR, we detected the expression of Nanog transcript in both tumor cell lines. In addition, our results reveal that HA binding to these tumor cells promotes Nanog protein association with CD44 followed by Nanog activation and the expression of pluripotent stem cell regulators (e.g. Rex1 and Sox2). Nanog also forms a complex with the "signal transducer and activator of transcription protein 3" (Stat-3) in the nucleus leading to Stat-3-specific transcriptional activation and multidrug transporter, MDR1 (P-glycoprotein) gene expression. Furthermore, we observed that HA-CD44 interaction induces ankyrin (a cytoskeletal protein) binding to MDR1 resulting in the efflux of chemotherapeutic drugs (e.g. doxorubicin and paclitaxel (Taxol)) and chemoresistance in these tumor cells. Overexpression of Nanog by transfecting tumor cells with Nanog cDNA stimulates Stat-3 transcriptional activation, MDR1 overexpression, and multidrug resistance. Down regulation of Nanog signaling or ankyrin function (by transfecting tumor cells with Nanog small interfering RNA or ankyrin repeat domain cDNA) not only blocks HA/CD44-mediated tumor cell behaviors but also enhances chemosensitivity. Taken together, these findings suggest that targeting HA/CD44-mediated Nanog-Stat-3 signaling pathways and ankyrin/cytoskeleton function may represent a novel approach to overcome chemotherapy resistance in some breast and ovarian tumor cells displaying stem cell marker properties during tumor progression.

MeSH Terms
ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism Ankyrins/metabolism Biological Transport Breast Neoplasms/drug therapy Cell Line, Tumor Disease Progression Female Gene Expression Regulation, Neoplastic Homeodomain Proteins/metabolism Humans Hyaluronan Receptors/chemistry Hyaluronic Acid/chemistry Nanog Homeobox Protein Ovarian Neoplasms/drug therapy STAT3 Transcription Factor/metabolism Stem Cells/metabolism
Chemicals
ABCB1 protein, human ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily B, Member 1 Ankyrins Homeodomain Proteins Hyaluronan Receptors NANOG protein, human Nanog Homeobox Protein STAT3 Transcription Factor STAT3 protein, human Hyaluronic Acid
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bourguignon Lilly Y W
Department of Medicine, University of California, San Francisco, and Endocrine Unit, Veterans Affairs Medical Center, San Francisco, California 94121, USA. lilly.bourguignon@ucsf.edu
Peyrollier Karine
Xia Weiliang
Gilad Eli
References (100)
100 references, click to expand
  1. What does Stat3 do?
    J Clin Invest. 2002 May;109(9):1143-8 PMID: 11994402
  2. FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes.
    J Clin Invest. 2003 Mar;111(5):627-37 PMID: 12618517
  3. Raft and cytoskeleton associations of an ABC transporter: P-glycoprotein.
    Cytometry A. 2004 Oct;61(2):105-16 PMID: 15382145
  4. Synuclein-gamma targeting peptide inhibitor that enhances sensitivity of breast cancer cells to antimicrotubule drugs.
    Cancer Res. 2007 Jan 15;67(2):626-33 PMID: 17234772
  5. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.
    Cell. 2003 May 30;113(5):643-55 PMID: 12787505
  6. Computational model of intracellular pharmacokinetics of paclitaxel.
    J Pharmacol Exp Ther. 2000 Jun;293(3):761-70 PMID: 10869374
  7. The effect of hyaluronate and its oligosaccharides on endothelial cell proliferation and monolayer integrity.
    Exp Cell Res. 1989 Jul;183(1):179-96 PMID: 2472284
  8. The role of hyaluronic acid in hemopoietic stem cell biology.
    Regen Med. 2006 Jul;1(4):437-45 PMID: 17465836
  9. Microtubule-targeted anticancer agents and apoptosis.
    Oncogene. 2003 Dec 8;22(56):9075-86 PMID: 14663486
  10. Ank3 (epithelial ankyrin), a widely distributed new member of the ankyrin gene family and the major ankyrin in kidney, is expressed in alternatively spliced forms, including forms that lack the repeat domain.
    J Cell Biol. 1995 Jul;130(2):313-30 PMID: 7615634
  11. Hyaluronan.
    FASEB J. 1992 Apr;6(7):2397-404 PMID: 1563592
  12. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins.
    Cell. 1986 Nov 7;47(3):371-80 PMID: 3768958
  13. The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer.
    Cancer Res. 2005 Aug 1;65(15):6660-7 PMID: 16061646
  14. Hyaluronidases: their genomics, structures, and mechanisms of action.
    Chem Rev. 2006 Mar;106(3):818-39 PMID: 16522010
  15. Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression.
    J Biol Chem. 2005 Mar 25;280(12):11961-72 PMID: 15655247
  16. Paclitaxel. An update of its use in the treatment of metastatic breast cancer and ovarian and other gynaecological cancers.
    Drugs Aging. 1998 Apr;12(4):305-34 PMID: 9571394
  17. Cell-to-cell adhesion modulates Stat3 activity in normal and breast carcinoma cells.
    Oncogene. 2004 Apr 8;23(15):2600-16 PMID: 15007380
  18. Expression of a multidrug-resistance gene in human tumors and tissues.
    Proc Natl Acad Sci U S A. 1987 Jan;84(1):265-9 PMID: 2432605
  19. Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth.
    J Biol Chem. 2001 Dec 28;276(52):48679-92 PMID: 11606575
  20. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration.
    J Biol Chem. 2001 Mar 9;276(10):7327-36 PMID: 11084024
  21. Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression.
    Mol Cell Biol. 2005 Mar;25(6):2475-85 PMID: 15743839
  22. Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein.
    Mol Cell Biol. 1999 Nov;19(11):7519-28 PMID: 10523640
  23. Distinct ankyrin isoforms at neuron cell bodies and nodes of Ranvier resolved using erythrocyte ankyrin-deficient mice.
    J Cell Biol. 1991 Sep;114(6):1243-59 PMID: 1832678
  24. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin.
    Biochem Pharmacol. 1999 Apr 1;57(7):727-41 PMID: 10075079
  25. Cytoskeletons and antimitotic agents developed in Japan.
    Anticancer Drug Des. 1999 Apr;14(2):133-41 PMID: 10405640
  26. The ankyrin-binding domain of CD44s is involved in regulating hyaluronic acid-mediated functions and prostate tumor cell transformation.
    Cell Motil Cytoskeleton. 1998;39(3):209-22 PMID: 9519902
  27. Hyaluronan: a multifunctional, megaDalton, stealth molecule.
    Curr Opin Cell Biol. 2000 Oct;12(5):581-6 PMID: 10978893
  28. Drug resistance in clinical practice: patterns of treatment failure in advanced breast and ovarian cancer.
    J Clin Oncol. 1986 Jun;4(6):952-7 PMID: 3519884
  29. Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications.
    Clin Cancer Res. 2007 Mar 1;13(5):1362-6 PMID: 17332277
  30. STATs and gene regulation.
    Science. 1997 Sep 12;277(5332):1630-5 PMID: 9287210
  31. Serum hyaluronan (hyaluronic acid) in breast cancer patients.
    Int J Cancer. 1990 Sep 15;46(3):388-90 PMID: 2394505
  32. Cancer stem cells: a new paradigm for understanding tumor progression and therapeutic resistance.
    Surgery. 2007 Apr;141(4):415-9 PMID: 17383517
  33. Prospective identification of tumorigenic breast cancer cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 PMID: 12629218
  34. Interaction between CD44 and the repeat domain of ankyrin promotes hyaluronic acid-mediated ovarian tumor cell migration.
    J Cell Physiol. 2000 May;183(2):182-95 PMID: 10737894
  35. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells.
    Cell. 1991 Apr 5;65(1):13-24 PMID: 1707342
  36. Stem cells and cancer: an overview.
    Stem Cell Rev. 2007 Dec;3(4):249-55 PMID: 17955391
  37. Expression of CD 44 s, CD 44 v 3 and CD 44 v 6 in benign and malignant breast lesions: correlation and colocalization with hyaluronan.
    Histopathology. 2005 Oct;47(4):420-8 PMID: 16178897
  38. Signaling properties of hyaluronan receptors.
    J Biol Chem. 2002 Feb 15;277(7):4589-92 PMID: 11717317
  39. The cell adhesion molecule, GP116, is a new CD44 variant (ex14/v10) involved in hyaluronic acid binding and endothelial cell proliferation.
    J Biol Chem. 1996 Sep 27;271(39):23853-64 PMID: 8798616
  40. Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis.
    Mol Carcinog. 2007 Aug;46(8):725-31 PMID: 17610223
  41. Cancer stem cells and individualized therapy.
    Cancer Genomics Proteomics. 2007 May-Jun;4(3):165-74 PMID: 17878520
  42. Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells.
    Cancer Res. 1997 Mar 1;57(5):978-87 PMID: 9041204
  43. CD44: the hyaluronan receptor.
    J Cell Sci. 1992 Oct;103 ( Pt 2):293-8 PMID: 1282514
  44. CD44 interaction with tiam1 promotes Rac1 signaling and hyaluronic acid-mediated breast tumor cell migration.
    J Biol Chem. 2000 Jan 21;275(3):1829-38 PMID: 10636882
  45. The identification of a new alternative exon with highly restricted tissue expression in transcripts encoding the mouse Pgp-1 (CD44) homing receptor. Comparison of all 10 variable exons between mouse, human, and rat.
    J Biol Chem. 1993 Jun 15;268(17):12235-8 PMID: 8509359
  46. Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation.
    J Biol Chem. 1997 Oct 31;272(44):27913-8 PMID: 9346940
  47. Survival and apoptotic signals in the action of microtubule-targeting antitumor drugs.
    IDrugs. 2005 Feb;8(2):127-43 PMID: 15696415
  48. Ankyrins: structure and function in normal cells and hereditary spherocytes.
    Semin Hematol. 1993 Apr;30(2):85-118 PMID: 8480190
  49. Heregulin-mediated ErbB2-ERK signaling activates hyaluronan synthases leading to CD44-dependent ovarian tumor cell growth and migration.
    J Biol Chem. 2007 Jul 6;282(27):19426-41 PMID: 17493932
  50. Isolation and characterization of cDNAs encoding human brain ankyrins reveal a family of alternatively spliced genes.
    J Cell Biol. 1991 Jul;114(2):241-53 PMID: 1830053
  51. MDR1, chemotherapy and chromatin remodeling.
    Cancer Biol Ther. 2004 Sep;3(9):819-24 PMID: 15326379
  52. Regulation of multidrug resistance in cancer cells by hyaluronan.
    J Biol Chem. 2003 Jul 11;278(28):25285-8 PMID: 12738783
  53. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor.
    Nat Med. 2004 Jan;10(1):55-63 PMID: 14702635
  54. CD44 isoform-cytoskeleton interaction in oncogenic signaling and tumor progression.
    Front Biosci. 1998 Jul 01;3:d637-49 PMID: 9634539
  55. The role and regulation of tumour-associated hyaluronan.
    Ciba Found Symp. 1989;143:150-9; discussion 159-69, 281-5 PMID: 2680343
  56. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues.
    Physiol Rev. 2001 Jul;81(3):1353-92 PMID: 11427698
  57. P-glycoprotein-actin association through ERM family proteins: a role in P-glycoprotein function in human cells of lymphoid origin.
    Blood. 2002 Jan 15;99(2):641-8 PMID: 11781249
  58. Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell-cycle control proteins.
    Nature. 1990 Mar 1;344(6261):36-42 PMID: 2137557
  59. Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma.
    Cancer. 2005 Nov 15;104(10):2255-65 PMID: 16228988
  60. Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells.
    Cell Motil Cytoskeleton. 1999;43(4):269-87 PMID: 10423269
  61. Ryanodine receptor-ankyrin interaction regulates internal Ca2+ release in mouse T-lymphoma cells.
    J Biol Chem. 1995 Jul 28;270(30):17917-22 PMID: 7629097
  62. Transcriptional regulation of nanog by OCT4 and SOX2.
    J Biol Chem. 2005 Jul 1;280(26):24731-7 PMID: 15860457
  63. ABC transporters: from microorganisms to man.
    Annu Rev Cell Biol. 1992;8:67-113 PMID: 1282354
  64. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway.
    Annu Rev Biochem. 1995;64:621-51 PMID: 7574495
  65. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells.
    Cell. 2003 May 30;113(5):631-42 PMID: 12787504
  66. Hyaluronan-CD44 promotes phospholipase C-mediated Ca2+ signaling and cisplatin resistance in head and neck cancer.
    Arch Otolaryngol Head Neck Surg. 2006 Jan;132(1):19-24 PMID: 16415424
  67. NANOGP8 is a retrogene expressed in cancers.
    FEBS J. 2006 Apr;273(8):1723-30 PMID: 16623708
  68. Effectiveness of Type I interferons in the treatment of multidrug resistant osteosarcoma cells.
    Int J Oncol. 2004 Feb;24(2):365-72 PMID: 14719113
  69. Clinical efficacy and prospects for use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers.
    Drugs. 1997;54 Suppl 4:22-9 PMID: 9361958
  70. Ankyrin regulation: an alternatively spliced segment of the regulatory domain functions as an intramolecular modulator.
    J Biol Chem. 1992 Sep 15;267(26):18966-72 PMID: 1388161
  71. Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin.
    Clin Cancer Res. 1998 Feb;4(2):389-98 PMID: 9516927
  72. Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor beta receptor I in metastatic breast tumor cells.
    J Biol Chem. 2002 Oct 18;277(42):39703-12 PMID: 12145287
  73. Hyaluronic acid secreted by mesothelial cells: a natural barrier to ovarian cancer cell adhesion.
    Clin Exp Metastasis. 1995 Sep;13(5):373-80 PMID: 7641421
  74. CD44v(3,8-10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.
    J Cell Physiol. 1998 Jul;176(1):206-15 PMID: 9618160
  75. Hyaluronan-cell interactions in cancer and vascular disease.
    J Biol Chem. 2002 Feb 15;277(7):4593-6 PMID: 11717318
  76. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons.
    Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12160-4 PMID: 1465456
  77. Signalling via integrins: implications for cell survival and anticancer strategies.
    Biochim Biophys Acta. 2007 Jan;1775(1):163-80 PMID: 17084981
  78. Mapping the binding sites of human erythrocyte ankyrin for the anion exchanger and spectrin.
    J Biol Chem. 1990 Jun 25;265(18):10589-96 PMID: 2141335
  79. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.
    Biochim Biophys Acta. 1976 Nov 11;455(1):152-62 PMID: 990323
  80. Hyaluronan in morphogenesis.
    Semin Cell Dev Biol. 2001 Apr;12(2):79-87 PMID: 11292373
  81. The influence of hyaluronan-CD44 interaction on topoisomerase II activity and etoposide cytotoxicity in head and neck cancer.
    Arch Otolaryngol Head Neck Surg. 2007 Mar;133(3):281-8 PMID: 17372087
  82. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together.
    Cancer. 2000 Jun 1;88(11):2619-28 PMID: 10861441
  83. CD44 interaction with ankyrin and IP3 receptor in lipid rafts promotes hyaluronan-mediated Ca2+ signaling leading to nitric oxide production and endothelial cell adhesion and proliferation.
    Exp Cell Res. 2004 Apr 15;295(1):102-18 PMID: 15051494
  84. Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating P-glycoprotein activity and PI3K/Akt pathway.
    Int J Cancer. 2008 Mar 1;122(5):1012-8 PMID: 17985348
  85. Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression.
    J Biol Chem. 2003 Aug 8;278(32):29420-34 PMID: 12748184
  86. Coexpression of CD44 variant (v10/ex14) and CD44S in human mammary epithelial cells promotes tumorigenesis.
    J Cell Physiol. 1997 May;171(2):152-60 PMID: 9130462
  87. cDNA sequence for human erythrocyte ankyrin.
    Proc Natl Acad Sci U S A. 1990 Mar;87(5):1730-4 PMID: 1689849
  88. CD44-mediated oncogenic signaling and cytoskeleton activation during mammary tumor progression.
    J Mammary Gland Biol Neoplasia. 2001 Jul;6(3):287-97 PMID: 11547898
  89. Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2.
    J Biol Chem. 2005 May 27;280(21):20310-5 PMID: 15784621
  90. RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response.
    Clin Cancer Res. 2003 Feb;9(2):827-36 PMID: 12576456
  91. Intracellular kinase inhibitors selected from combinatorial libraries of designed ankyrin repeat proteins.
    J Biol Chem. 2005 Jul 1;280(26):24715-22 PMID: 15851475
  92. Cell-cell fusion as a means to establish pluripotency.
    Ernst Schering Res Found Workshop. 2006;(60):35-45 PMID: 16903415
  93. Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells.
    Gynecol Oncol. 2000 Oct;79(1):67-73 PMID: 11006034
  94. Stat3 activation by Src induces specific gene regulation and is required for cell transformation.
    Mol Cell Biol. 1998 May;18(5):2545-52 PMID: 9566874
  95. Hyaluronan and the interaction between CD44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer.
    Arch Otolaryngol Head Neck Surg. 2006 Jul;132(7):771-8 PMID: 16847188
  96. Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell.
    Cancer Lett. 2007 Jul 18;252(2):225-34 PMID: 17276588
  97. New CD44 splice variants associated with human breast cancers.
    J Cell Physiol. 1995 Jan;162(1):127-33 PMID: 7529235
  98. p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression.
    Nat Cell Biol. 2005 Feb;7(2):165-71 PMID: 15619621
  99. Hyaluronan-CD44 interaction with neural Wiskott-Aldrich syndrome protein (N-WASP) promotes actin polymerization and ErbB2 activation leading to beta-catenin nuclear translocation, transcriptional up-regulation, and cell migration in ovarian tumor cells.
    J Biol Chem. 2007 Jan 12;282(2):1265-80 PMID: 17092940
  100. STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3-inducible targets linked to cell survival and proliferation.
    J Clin Pathol. 2007 Feb;60(2):173-9 PMID: 17264243
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M800109200
Email
lilly.bourguignon@ucsf.edu
Published
2008-06-20
Epub
2008-00-25
Pages
17635-51
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2427357
Subset
IM
Grants
NCI NIH HHS · R01 CA78633 · United States
NCI NIH HHS · R01 CA078633-10 · United States
NCI NIH HHS · R01 CA066163-14 · United States
NCI NIH HHS · R01 CA66163 · United States
NIAMS NIH HHS · P01 AR039448 · United States
NIAMS NIH HHS · P01 AR039448-190007 · United States
NCI NIH HHS · R01 CA078633 · United States
NIAMS NIH HHS · P01 AR39448 · United States
NCI NIH HHS · R01 CA066163 · United States
External Links
PubMed source DOI: 10.1074/jbc.M800109200 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2