Skip to main content
SpringerLink
Log in

GSK-3β Inhibition in Pancreatic Cancer

  • Chapter
Pancreatic Cancer

Part of the book series: M. D. Anderson Solid Tumor Oncology Series ((MDA))

GSK-3 (glycogen synthase kinase-3) has emerged as a potential therapeutic target for the treatment of Alzheimer’s disease, diabetes mellitus, and cancer. Although the prominent role of GSK-3 in the APC/β-catenin destruction complex implies that inhibition of GSK-3 could possibly lead to tumor promotion through the activation of the oncogene β-catenin, several studies contradict this concern. A greater understanding presently exists of the molecular mechanisms by which GSK-3β regulates tumor cell proliferation and survival in several human malignancies, including pancreatic cancer. In particular, GSK-3β has been discovered to be a critical regulator of NFκB nuclear activity, supporting the strategy of inhibiting GSK-3β specifically in cancers with constitutively active NFκB. This chapter reviews the current understanding of the role of GSK-3 in human cancer and its potential as a therapeutic target.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Plyte Se, Hughes K, Nikolakaki E, et al. 1992, Glycogen synthase kinase-3: functions in onco-genesis and development. Biochim Biophys Acta 1114(2-3):147–162.

    CAS  PubMed  Google Scholar 

  2. Doble BW, Woodgett Jr. 2003, GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116(Pt 7):1175–1186.

    Article  CAS  PubMed  Google Scholar 

  3. Woodgett Jr. 1990, Molecular cloning and expression of glycogen synthase kinase-3/factor A. Embo J 9(8):2431–2438.

    CAS  PubMed  Google Scholar 

  4. Polakis P. 2000, Wnt signaling and cancer. Genes Dev 14(15):1837–1851.

    CAS  PubMed  Google Scholar 

  5. Hoeflich KP, Luo J, Rubie EA, et al. 2000, Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406(6791):86–90.

    Article  CAS  PubMed  Google Scholar 

  6. Ding VW, Chen R, McCormick F. 2000, Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. J Biol Chem 275(42):32475–32481.

    Article  CAS  PubMed  Google Scholar 

  7. Patel S, Doble BW Jr. 2004, Glycogen synthase kinase-3 in insulin and Wnt signalling: a double-edged sword? Biochem Soc Trans 32(Pt 5):803–808.

    CAS  PubMed  Google Scholar 

  8. Cross DA, Alessi DR, Cohen P, et al. 1995, Inhibition of glycogen synthase kinase-3 by insu-lin mediated by protein kinase B. Nature 378(6559):785–789.

    Article  CAS  PubMed  Google Scholar 

  9. Altomare DA, Testa JR. 2005, Perturbations of the AKT signaling pathway in human cancer. Oncogene 24(50):7455–7464.

    Article  CAS  PubMed  Google Scholar 

  10. Cheng JQ, Ruggeri B, Klein WM, et al. 1996, Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 93(8):3636–3641.

    Article  CAS  PubMed  Google Scholar 

  11. Ougolkov AV, Fernandez-Zapico ME, Savoy DN, et al. 2005, Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res 65(6):2076–2081.

    Article  CAS  PubMed  Google Scholar 

  12. Shakoori A, Ougolkov A, Yu ZW, et al. 2005, Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun 334(4):1365–1373.

    Article  CAS  PubMed  Google Scholar 

  13. Ryves WJ, Harwood AJ. 2003, The interaction of glycogen synthase kinase-3 (GSK-3) with the cell cycle. Prog Cell Cycle Res 5:489–495.

    PubMed  Google Scholar 

  14. Cohen Y, Chetrit A, Cohen Y, et al. 1998, Cancer morbidity in psychiatric patients: influence of lithium carbonate treatment. Med Oncol 15(1):32–36.

    Article  CAS  PubMed  Google Scholar 

  15. Erdal E, Ozturk N, Cagatay T, et al. 2005, Lithium-mediated downregulation of PKB/Akt and cyclin E with growth inhibition in hepatocellular carcinoma cells. Int J Cancer 115 (6): 903–910.

    Article  CAS  PubMed  Google Scholar 

  16. Hezel AF, Kimmelman AC, Stanger BZ, et al. 2006, Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 20(10):1218–1249.

    Article  CAS  PubMed  Google Scholar 

  17. Feinman R, Koury J, Thames M, et al. 1999, Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 93(9):3044–3052.

    CAS  PubMed  Google Scholar 

  18. Baron F, Turhan AG, Giron-Michel J, et al. 2002, Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression. Blood 99(6):2107–2113.

    Article  CAS  PubMed  Google Scholar 

  19. Griffin JD. 2001, Leukemia stem cells and constitutive activation of NF-kappaB. Blood 98 (8):2291.

    Article  CAS  PubMed  Google Scholar 

  20. Kordes U, Krappmann D, Heissmeyer V, et al. 2000, Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14 (3): 399–402.

    Article  CAS  PubMed  Google Scholar 

  21. Nakshatri H, Bhat-Nakshatri P, Martin DA, et al. 1997, Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17 (7):3629–3639.

    CAS  PubMed  Google Scholar 

  22. Palayoor ST, Youmell MY, Calderwood SK, et al. 1999, Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18 (51):7389–7394.

    Article  CAS  PubMed  Google Scholar 

  23. Wang W, Abbruzzese JL, Evans DB, et al. 1999, The nuclear factor-kappa B RelA transcrip-tion factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 5(1):119–127.

    CAS  PubMed  Google Scholar 

  24. Beg AA, Baltimore D. 1996, An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274(5288):782–784.

    Article  CAS  PubMed  Google Scholar 

  25. Wang CY, Cusack JC Jr, Liu RB Jr. 1999, Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med 5 (4): 412–417.

    Article  PubMed  Google Scholar 

  26. Andela VB, Schwarz EM, Puzas JE, et al. 2000, Tumor metastasis and the reciprocal regula-tion of prometastatic and antimetastatic factors by nuclear factor kappaB. Cancer Res 60 (23):6557–6562.

    CAS  PubMed  Google Scholar 

  27. Pahl HL. 1999, Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866.

    Article  CAS  PubMed  Google Scholar 

  28. Aggarwal BB. 2004, Nuclear factor-kappaB: the enemy within. Cancer Cell 6 (3): 203–208.

    Article  CAS  PubMed  Google Scholar 

  29. Karin M, Cao Y, Greten FL, et al. 2002, NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2(4):301–310.

    Article  CAS  PubMed  Google Scholar 

  30. Beg AA, Sha WC, Bronson RT, et al. 1995, Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376(6536):167–170.

    Article  CAS  PubMed  Google Scholar 

  31. Li Q, Van Antwerp D, Mercurio F, et al. 1999, Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284(5412):321–325.

    Article  CAS  PubMed  Google Scholar 

  32. Liao X, Zhang L, Thrasher JB, et al. 2003, Glycogen synthase kinase-3beta suppression elimi-nates tumor necrosis factor-related apoptosis-inducing ligand resistance in prostate cancer. Mol Cancer Ther 2(11):1215–1222.

    CAS  PubMed  Google Scholar 

  33. Mazor M, Kawano Y, Zhu H, et al. 2004, I nhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth. Oncogene 23(47):7882–7892.

    Article  CAS  PubMed  Google Scholar 

  34. Ougolkov AV, Fernandez-Zapico ME, Bilim VN, et al. 2006, Aberrant nuclear accumulation of glycogen synthase kinase-3beta in human pancreatic cancer: association with kinase activ-ity and tumor dedifferentiation. Clin Cancer Res 12(17):5074–5081.

    Article  CAS  PubMed  Google Scholar 

  35. Deng J, Miller SA, Wang HY, et al. 2002, Beta-catenin interacts with and inhibits NF-kappa B in human colon and breast cancer. Cancer Cell 2 (4): 323–334.

    Article  CAS  PubMed  Google Scholar 

  36. Deng J, Xia W, Miller SA, et al. 2004, Cross-regulation of NF-kappaB by the APC/GSK-3beta/beta-catenin pathway. Mol Carcinog 39(3):139–146.

    Article  CAS  PubMed  Google Scholar 

  37. Ghosh JC, Altieri DC. 2005, Activation of p53-dependent apoptosis by acute ablation of gly-cogen synthase kinase-3beta in colorectal cancer cells. Clin Cancer Res 11(12):4580–4588.

    Article  CAS  PubMed  Google Scholar 

  38. Collett GP, Campbell FC. 2004, Curcumin induces c-jun N-terminal kinase-dependent apop-tosis in HCT116 human colon cancer cells. Carcinogenesis 25(11):2183–2189.

    Article  CAS  PubMed  Google Scholar 

  39. Thisse C, Perrin-Schmitt F, Stoetzel C, et al. 1991, Sequence-specific transactivation of the Drosophila twist gene by the dorsal gene product. Cell 65(7):1191–1201.

    Article  CAS  PubMed  Google Scholar 

  40. Tergaonkar V, Pando M, Vafa O, et al. 2002, p53 Stabilization is decreased upon NFkappaB activa-tion: a role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell 1 (5):493–503.

    Article  CAS  PubMed  Google Scholar 

  41. Beals CR, Sheridan CM, Turck CW, et al. 1997, Nuclear export of NF-ATc enhanced by gly-cogen synthase kinase-3. Science 275(5308):1930–1934.

    Article  CAS  PubMed  Google Scholar 

  42. Ougolkov AV, Bone ND, Fernandez-Zapico ME, et al. 2007, Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor {kappa}B target genes and induction of apoptosis in chronic lymphocytic leukemia B cells. Blood 110(2):735–742.

    Article  CAS  PubMed  Google Scholar 

  43. Kern SE. 2000, Molecular genetic alterations in ductal pancreatic adenocarcinomas. Med Clin North Am 84(3):691–695, xi.

    Article  CAS  PubMed  Google Scholar 

  44. Arlt A, Gehrz A, Muerkoster S, et al. 2003, Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene 22 (21):3243–3251.

    Article  CAS  PubMed  Google Scholar 

  45. Demarchi F, Bertoli C, Sandy P, et al. 2003, Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability. J Biol Chem 278(41):39583–39590.

    Article  CAS  PubMed  Google Scholar 

  46. Maitra A, Kern SE, Hruban RH. 2006, Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol 20(2):211–226.

    Article  CAS  PubMed  Google Scholar 

  47. Rask K, Nilsson A, Brannstrom M, et al. 2003, Wnt-signalling pathway in ovarian epithelial tumours: increased expression of beta-catenin and GSK3beta. Br J Cancer 89(7):1298–1304.

    Article  CAS  PubMed  Google Scholar 

  48. Gotoh JObata M, Yoshie M, et al. 2003, Cyclin D1 over-expression correlates with beta-cat-enin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. Carcinogenesis 24(3):435–442.

    Article  Google Scholar 

  49. Beals CR, Sheridan CM, Turck CW, et al. 1997, Nuclear export of NF-ATc enhanced by gly-cogen synthase kinase-3. Science 275(5308):1930–1934.

    Article  CAS  PubMed  Google Scholar 

  50. Wei W, Jin J, Schlisio S, et al. 2005, The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 8 (1): 25–33.

    Article  CAS  PubMed  Google Scholar 

  51. De Ketelaere A, Vermeulen L, Vialard J, et al. 2004, I nvolvement of GSK-3beta in TWEAK-mediated NF-kappaB activation. FEBS Lett 566(1-3):60–64.

    Article  PubMed  Google Scholar 

  52. Senderowicz AM. 2003, Novel small molecule cyclin-dependent kinases modulators in human clinical trials. Cancer Biol Ther 2(4 Suppl 1):S84–95.

    CAS  PubMed  Google Scholar 

  53. Leclerc S, Garnier M, Hoessel R, et al. 2001, Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 276(1):251–260.

    Article  CAS  PubMed  Google Scholar 

  54. Kim DM, Koo SY, Jeon K, et al. 2003, Rapid induction of apoptosis by combination of fla-vopiridol and tumor necrosis factor (TNF)-alpha or TNF-related apoptosis-inducing ligand in human cancer cell lines. Cancer Res 63(3):621–626.

    CAS  PubMed  Google Scholar 

  55. Schwabe RF, Brenner DA. 2002, Role of glycogen synthase kinase-3 in TNF-alpha-induced NF-kappaB activation and apoptosis in hepatocytes. Am J Physiol Gastrointest Liver Physiol 283 (1):G204–211.

    CAS  PubMed  Google Scholar 

  56. Kitada S, Zapata JM, Andreeff M, et al. 2000, Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 96(2):393–397.

    CAS  PubMed  Google Scholar 

  57. Wittmann S, Bali P, Donapaty S, et al. 2003, Flavopiridol down-regulates antiapoptotic pro-teins and sensitizes human breast cancer cells to epothilone B-induced apoptosis. Cancer Res 63 (1):93–99.

    CAS  PubMed  Google Scholar 

  58. Salgia R, Skarin AT. 1998, Molecular abnormalities in lung cancer. J Clin Oncol 16(3):1207–1217.

    CAS  PubMed  Google Scholar 

  59. Joseph B, Marchetti P, Formstecher P, et al. 2002, Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment. Oncogene 21(1):65–77.

    Article  CAS  PubMed  Google Scholar 

  60. Ougolkov AV, Bone ND, Fernandez-Zapico ME, et al. 2007, Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells. Blood 110(2):735–742.

    Article  CAS  PubMed  Google Scholar 

  61. Arlt A, Vorndamm J, Breitenbroich M, et al. 2001, Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. Oncogene 20(7):859–868.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology-Oncology, Mayo Clinic College of Medicine, Jacksonville, Florida, USA

    George P. Kim MD

  2. Division of Oncology Research, Mayo Clinic, Rochester, Minnesota, USA

    Daniel D. Billadeau MD

Authors
  1. George P. Kim MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel D. Billadeau MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of California San Diego, La Jolla, CA, USA

    Andrew M. Lowy

  2. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Steven D. Leach

  3. Wayne State University, Detroit, MI, USA

    Philip A. Philip

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Kim, G.P., Billadeau, D.D. (2008). GSK-3β Inhibition in Pancreatic Cancer. In: Lowy, A.M., Leach, S.D., Philip, P.A. (eds) Pancreatic Cancer. M. D. Anderson Solid Tumor Oncology Series. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-69252-4_37

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-69252-4_37

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-69250-0

  • Online ISBN: 978-0-387-69252-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation