Home LiteratureArticle Details
PMID: 19483724 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and inhibition of migration and invasion of breast cancer cells.

Oncogene ·Vol. 28 ·No. 29 ·2009-07-23 ·Pages 2621-33

Taliaferro-Smith L, Nagalingam A, Zhong D, Zhou W, Saxena NK, Sharma D

Abstract

Adiponectin is widely known as an adipocytokine with therapeutic potential for its markedly protective function in the pathogenesis of obesity-related disorders, metabolic syndrome, systemic insulin resistance, cardiovascular disease and more recently carcinogenesis. In the present study, we show that adiponectin inhibits adhesion, invasion and migration of breast cancer cells. Further analysis of the underlying molecular mechanisms revealed that adiponectin treatment increased AMP-activated protein kinase (AMPK) phosphorylation and activity as evident by increased phosphorylation of downstream target of AMPK, acetyl-coenzyme A carboxylase and inhibition of p70S6 kinase (S6K). Intriguingly, we discovered that adiponectin treatment increases the expression of tumor suppressor gene LKB1 in breast cancer cells. Overexpression of LKB1 in breast cancer cells further increased adiponectin-mediated phosphorylation of AMPK. Using isogenic LKB1 knockdown cell line pair, we found that LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and more importantly, inhibition of adhesion, migration and invasion of breast cancer cells. Taken together these data present a novel mechanism involving specific upregulation of tumor suppressor gene LKB1 by which adiponectin inhibits adhesion, invasion and migration of breast cancer cells. Our findings indicate the possibility of using adiponectin analogues to inhibit invasion and migration of breast cancer cells.

MeSH Terms
AMP-Activated Protein Kinase Kinases Adiponectin/pharmacology Breast Neoplasms/enzymology,pathology Cell Adhesion/drug effects Cell Line, Tumor Cell Movement/drug effects Enzyme Activation Gene Expression Regulation, Neoplastic/drug effects Humans Neoplasm Invasiveness Phosphorylation/drug effects Protein Kinases/metabolism Protein Serine-Threonine Kinases/genetics Ribosomal Protein S6 Kinases, 70-kDa/metabolism TOR Serine-Threonine Kinases
Chemicals
Adiponectin Protein Kinases MTOR protein, human Protein Serine-Threonine Kinases Ribosomal Protein S6 Kinases, 70-kDa STK11 protein, human TOR Serine-Threonine Kinases AMP-Activated Protein Kinase Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Taliaferro-Smith L
Department of Hematology and Medical Oncology, Winship Cancer Institute, Atlanta, GA 30322, USA.
Nagalingam A
Zhong D
Zhou W
Saxena N K
Sharma D
References (71)
71 references, click to expand
  1. Association of serum adiponectin levels with breast cancer risk.
    Clin Cancer Res. 2003 Nov 15;9(15):5699-704 PMID: 14654554
  2. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.
    Nature. 2003 Jun 12;423(6941):762-9 PMID: 12802337
  3. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression.
    Endocr Relat Cancer. 2007 Jun;14(2):189-206 PMID: 17639037
  4. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin.
    Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10308-13 PMID: 15210937
  5. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha.
    Diabetes. 2006 Sep;55(9):2562-70 PMID: 16936205
  6. Adipose tissue, adipokines, and inflammation.
    J Allergy Clin Immunol. 2005 May;115(5):911-9; quiz 920 PMID: 15867843
  7. Antiproliferative effect of adiponectin on MCF7 breast cancer cells: a potential hormonal link between obesity and cancer.
    Horm Metab Res. 2007 Jan;39(1):9-13 PMID: 17226107
  8. Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner.
    J Biol Chem. 2005 May 6;280(18):18341-7 PMID: 15734737
  9. LKB1 is necessary for Akt-mediated phosphorylation of proapoptotic proteins.
    Cancer Res. 2008 Sep 15;68(18):7270-7 PMID: 18794113
  10. Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1.
    J Mol Signal. 2008 Dec 01;3:18 PMID: 19046439
  11. Adiponectin and leptin expression in primary ductal breast cancer and in adjacent healthy epithelial and myoepithelial tissue.
    Histopathology. 2008 Oct;53(4):484-7 PMID: 18983614
  12. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
    Nat Genet. 1998 Jan;18(1):38-43 PMID: 9425897
  13. Obesity, adipocytokines, and insulin resistance in breast cancer.
    Obes Rev. 2004 Aug;5(3):153-65 PMID: 15245384
  14. Adiponectin mediates an antiproliferative response in human MDA-MB 231 breast cancer cells.
    Oncol Rep. 2008 Oct;20(4):971-7 PMID: 18813842
  15. Adiponectin stimulates human osteoblasts proliferation and differentiation via the MAPK signaling pathway.
    Exp Cell Res. 2005 Sep 10;309(1):99-109 PMID: 15963981
  16. MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm.
    EMBO J. 2003 Oct 1;22(19):5102-14 PMID: 14517248
  17. Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model.
    Breast Cancer Res Treat. 2009 Jan;113(1):101-11 PMID: 18256928
  18. Adiponectin: a link between obesity and cancer.
    Expert Opin Investig Drugs. 2006 Aug;15(8):917-31 PMID: 16859394
  19. AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells.
    Biochem Biophys Res Commun. 2004 Nov 26;324(4):1204-9 PMID: 15504342
  20. Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome.
    Biochem J. 2002 Mar 1;362(Pt 2):481-90 PMID: 11853558
  21. Total and high-molecular-weight adiponectin in breast cancer: in vitro and in vivo studies.
    J Clin Endocrinol Metab. 2007 Mar;92(3):1041-8 PMID: 17192291
  22. Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women.
    Cancer Causes Control. 2002 May;13(4):325-32 PMID: 12074502
  23. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma.
    J Biochem. 1996 Oct;120(4):803-12 PMID: 8947845
  24. AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer.
    J Physiol. 2006 Jul 1;574(Pt 1):63-71 PMID: 16613876
  25. Chutes and Ladders: the search for protein kinases that act on AMPK.
    Trends Biochem Sci. 2006 Jan;31(1):13-6 PMID: 16356723
  26. Relation of body mass index to tumor markers and survival among young women with invasive ductal breast carcinoma.
    Cancer. 2001 Aug 15;92(4):720-9 PMID: 11550140
  27. Adiponectin and protection against type 2 diabetes mellitus.
    Lancet. 2003 Jan 18;361(9353):226-8 PMID: 12547549
  28. Adiponectin: A novel adipokine linking adipocytes and vascular function.
    J Clin Endocrinol Metab. 2004 Jun;89(6):2563-8 PMID: 15181024
  29. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells.
    Cancer Res. 2007 Mar 15;67(6):2497-507 PMID: 17363567
  30. LKB1 protein expression in human breast cancer.
    Appl Immunohistochem Mol Morphol. 2006 Jun;14(2):146-53 PMID: 16785781
  31. Analysis of the LKB1-STRAD-MO25 complex.
    J Cell Sci. 2004 Dec 15;117(Pt 26):6365-75 PMID: 15561763
  32. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.
    J Biol Chem. 2003 Jan 24;278(4):2461-8 PMID: 12431986
  33. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.
    Cancer Res. 2006 Nov 1;66(21):10269-73 PMID: 17062558
  34. LKB1; linking cell structure and tumor suppression.
    Oncogene. 2008 Nov 24;27(55):6908-19 PMID: 19029933
  35. Adiponectin and metabolic syndrome.
    Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):29-33 PMID: 14551151
  36. Metastasis: a therapeutic target for cancer.
    Nat Clin Pract Oncol. 2008 Apr;5(4):206-19 PMID: 18253104
  37. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD.
    EMBO J. 2003 Jun 16;22(12):3062-72 PMID: 12805220
  38. A novel serum protein similar to C1q, produced exclusively in adipocytes.
    J Biol Chem. 1995 Nov 10;270(45):26746-9 PMID: 7592907
  39. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size.
    Trends Biochem Sci. 2006 Jun;31(6):342-8 PMID: 16679021
  40. Adiponectin stimulates Wnt inhibitory factor-1 expression through epigenetic regulations involving the transcription factor specificity protein 1.
    Carcinogenesis. 2008 Nov;29(11):2195-202 PMID: 18701434
  41. LKB1-dependent signaling pathways.
    Annu Rev Biochem. 2006;75:137-63 PMID: 16756488
  42. The tumor suppressor gene LKB1 is associated with prognosis in human breast carcinoma.
    Clin Cancer Res. 2002 Jul;8(7):2085-90 PMID: 12114407
  43. Demonstration of adiponectin receptors 1 and 2 mRNA expression in human breast cancer cells.
    Cancer Lett. 2007 Jun 8;250(2):229-36 PMID: 17123704
  44. Effects of adiponectin on breast cancer cell growth and signaling.
    Br J Cancer. 2008 Jan 29;98(2):370-9 PMID: 18182989
  45. New roles for the LKB1-->AMPK pathway.
    Curr Opin Cell Biol. 2005 Apr;17(2):167-73 PMID: 15780593
  46. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3.
    J Biol Chem. 2007 May 4;282(18):13316-25 PMID: 17344214
  47. Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice.
    Cancer Res. 2006 Dec 1;66(23):11462-70 PMID: 17145894
  48. Growth-inhibitory effect of adiponectin via adiponectin receptor 1 on human breast cancer cells through inhibition of S-phase entry without inducing apoptosis.
    Breast Cancer Res Treat. 2008 Dec;112(3):405-10 PMID: 18163210
  49. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.
    Nat Med. 2001 Aug;7(8):947-53 PMID: 11479628
  50. The AMP-activated protein kinase pathway--new players upstream and downstream.
    J Cell Sci. 2004 Nov 1;117(Pt 23):5479-87 PMID: 15509864
  51. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.
    Nat Med. 2002 Nov;8(11):1288-95 PMID: 12368907
  52. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.
    Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2005-10 PMID: 11172066
  53. Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans.
    Metab Syndr Relat Disord. 2008 Jun;6(2):87-102 PMID: 18510434
  54. Low plasma adiponectin levels predict progression of coronary artery calcification.
    Circulation. 2005 Feb 15;111(6):747-53 PMID: 15699257
  55. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice.
    J Clin Invest. 2003 Jul;112(1):91-100 PMID: 12840063
  56. Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer.
    Nat Clin Pract Endocrinol Metab. 2007 Apr;3(4):345-54 PMID: 17377617
  57. Adiponectin and cancer: a systematic review.
    Br J Cancer. 2006 May 8;94(9):1221-5 PMID: 16570048
  58. Serum adiponectin and leptin levels in Taiwanese breast cancer patients.
    Cancer Lett. 2006 Jun 8;237(1):109-14 PMID: 16019138
  59. Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor.
    Cancer Res. 2008 Dec 1;68(23):9712-22 PMID: 19047149
  60. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).
    Biochem Biophys Res Commun. 1996 Apr 16;221(2):286-9 PMID: 8619847
  61. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro.
    Cell Cycle. 2009 Mar 15;8(6):909-15 PMID: 19221498
  62. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress.
    Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35 PMID: 14985505
  63. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.
    N Engl J Med. 2003 Apr 24;348(17):1625-38 PMID: 12711737
  64. AdipoQ is a novel adipose-specific gene dysregulated in obesity.
    J Biol Chem. 1996 May 3;271(18):10697-703 PMID: 8631877
  65. Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1).
    Hum Mol Genet. 2002 Jun 15;11(13):1497-504 PMID: 12045203
  66. Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics.
    J Clin Endocrinol Metab. 2005 Jun;90(6):3665-72 PMID: 15769985
  67. Adiponectin and breast cancer risk.
    J Clin Endocrinol Metab. 2004 Mar;89(3):1102-7 PMID: 15001594
  68. Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth.
    J Biol Chem. 2001 Jun 1;276(22):19469-82 PMID: 11297520
  69. The expanding TOR signaling network.
    Curr Opin Cell Biol. 2005 Apr;17(2):158-66 PMID: 15780592
  70. AMPK, the metabolic syndrome and cancer.
    Trends Pharmacol Sci. 2005 Feb;26(2):69-76 PMID: 15681023
  71. Adiponectin mediates antiproliferative and apoptotic responses in human MCF7 breast cancer cells.
    Biochem Biophys Res Commun. 2006 Jun 23;345(1):271-9 PMID: 16678125
Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2009.129
Published
2009-07-23
Epub
2009-00-01
Pages
2621-33
Language
English
Region
England
NLM ID
8711562
PMCID
PMC2945727
Subset
IM
Grants
NIDDK NIH HHS · K01 DK077137-02 · United States
NIDDK NIH HHS · K01 DK077137-05 · United States
NIDDK NIH HHS · R03 DK089130-02 · United States
NIDDK NIH HHS · R03 DK089130 · United States
NIDDK NIH HHS · K01 DK077137-01A1 · United States
NIDDK NIH HHS · K01 DK076742 · United States
NCI NIH HHS · R01CA131294 · United States
NIDDK NIH HHS · K01DK076742 · United States
NIDDK NIH HHS · K01 DK077137-04 · United States
NCI NIH HHS · R01 CA131294 · United States
NIDDK NIH HHS · R03 DK089130-03 · United States
NIDDK NIH HHS · K01 DK077137 · United States
NCI NIH HHS · 5P01CA116676-030002 · United States
External Links
PubMed source DOI: 10.1038/onc.2009.129 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: [email protected]

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