Skip to main content
SpringerLink
Log in

PF-3758309, p21-activated kinase 4 inhibitor, suppresses migration and invasion of A549 human lung cancer cells via regulation of CREB, NF-κB, and β-catenin signalings

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Migration and invasion comprise key steps in cancer metastasis. Through the migration and invasion into and out of lymphatic and/or blood vessels, cancer cells can be spread out into the tissues in remote site from the origin. Degradation of extracellular matrix (ECM) must be preceded prior to the metastasis of cancer cells. Matrix metalloproteinases (MMP) can degrade ECM, thus allow cells to migrate from the original site. Among MMPs, two gelatinase MMP-2 and MMP-9 play particularly important roles in ECM degradation. Here, we report that recently developed p21-activated kinase 4 inhibitor PF-3758309 shows anti-metastatic effect in A549 human lung cancer cell. PF-3758309 suppresses CREB, NF-κB, and β-catenin pathways, which are well known to be closely related with cell migration. This leads to the downregulation of MMP-2/MMP-9 expressions and the inhibition of A549 lung cancer metastasis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Baeuerle PA, Baltimore D (1996) NF-kappa B: 10 years after. Cell 87:13–20

    Article  CAS  PubMed  Google Scholar 

  2. Baeuerle PA, Henkel T (1994) Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12:141–179

    Article  CAS  PubMed  Google Scholar 

  3. Basset P, Okada A, Chenard MP, Kannan R, Stoll I, Anglard P, Bellocq JP, Rio MC (1997) Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol 15:535–541

    Article  CAS  PubMed  Google Scholar 

  4. Bierbaum S, Hintze V, Scharnweber D (2012) Functionalization of biomaterial surfaces using artificial extracellular matrices. Biomatter 2:132–141

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bokoch GM (2003) Biology of the p21-activated kinases. Annu Rev Biochem 72:743–781

    Article  CAS  PubMed  Google Scholar 

  6. Brabletz T, Jung A, Dag S, Reu S, Kirchner T (2000) β-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma. Verh Dtsch Ges Pathol 84:175–181

    CAS  PubMed  Google Scholar 

  7. Callow MG, Clairvoyant F, Zhu S, Schryver B, Whyte DB, Bischoff JR, Jallal B, Smeal T (2002) Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J Biol Chem 277:550–558

    Article  CAS  PubMed  Google Scholar 

  8. Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25:9–34

    Article  CAS  PubMed  Google Scholar 

  9. Eswaran J, Soundararajan M, Knapp S (2009) Targeting group II PAKs in cancer and metastasis. Cancer Metastasis Rev 28:209–217

    Article  CAS  PubMed  Google Scholar 

  10. Eswaran J, Soundararajan M, Kumar R, Knapp S (2008) UnPAKing the class differences among p21-activated kinases. Trends Biochem Sci 33:394–403

    Article  CAS  PubMed  Google Scholar 

  11. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  CAS  PubMed  Google Scholar 

  12. Henkel T, Zabel U, van Zee K, Müller JM, Fanning E, Baeuerle PA (1992) Intramolecular masking of the nuclear location signal and dimerization domain in the precursor for the p50 NF-kappa B subunit. Cell 68:1121–1133

    Article  CAS  PubMed  Google Scholar 

  13. Hlubek F, Spaderna S, Jung A, Kirchner T, Brabletz T (2004) Beta-catenin activates a coordinated expression of the proinvasive factors laminin-5 gamma2 chain and MT1-MMP in colorectal carcinomas. Int J Cancer 108:321–326

    Article  CAS  PubMed  Google Scholar 

  14. Johnsen M, Lund LR, Rømer J, Almholt K, Danø K (1998) Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol 10:667–671

    Article  CAS  PubMed  Google Scholar 

  15. Karin M, Yamamoto Y, Wang QM (2004) The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3:17–26

    Article  CAS  PubMed  Google Scholar 

  16. Kolligs FT, Bommer G, Göke B (2002) Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion 66:131–144

    Article  CAS  PubMed  Google Scholar 

  17. Kumar R, Gururaj AE, Barnes CJ (2006) p21-activated kinases in cancer. Nat Rev Cancer 6:459–471

    Article  CAS  PubMed  Google Scholar 

  18. Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2:599–609

    Article  CAS  PubMed  Google Scholar 

  19. Meyer TE, Habener JF (1993) Cyclic adenosine 3′,5′-monophosphate response element binding protein (CREB) and related transcription-activating deoxyribonucleic acid-binding proteins. Endocr Rev 14:269–290

    CAS  PubMed  Google Scholar 

  20. Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, Dagostino E, Knighton D, Loi CM, Zager M, Kraynov E, Popoff I, Christensen JG, Martinez R, Kephart SE, Marakovits J, Karlicek S, Bergqvist S, Smeal T (2010) Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci USA 107:9446–9451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nyberg P, Salo T, Kalluri R (2008) Tumor microenvironment and angiogenesis. Front Biosci 13:6537–6553

    Article  CAS  PubMed  Google Scholar 

  22. Park MH, Lee HS, Lee CS, You ST, Kim DJ, Park BH, Kang MJ, Heo WD, Shin EY, Schwartz MA, Kim EG (2013) p21-activated kinase 4 promotes prostate cancer progression through CREB. Oncogene 32:2475–2482

    Article  CAS  PubMed  Google Scholar 

  23. Pitts TM, Kulikowski GN, Tan AC, Murray BW, Arcaroli JJ, Tentler JJ, Spreafico A, Selby HM, Kachaeva MI, McPhillips KL, Britt BC, Bradshaw-Pierce EL, Messersmith WA, Varella-Garcia M, Eckhardt SG (2013) Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models. Front Pharmacol 4:35

    Article  PubMed  PubMed Central  Google Scholar 

  24. Qu J, Cammarano MS, Shi Q, Ha KC, de Lanerolle P, Minden A (2001) Activated PAK4 regulates cell adhesion and anchorage-independent growth. Mol Cell Biol 21:3523–3533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qu J, Li X, Novitch BG, Zheng Y, Kohn M, Xie JM, Kozinn S, Bronson R, Beg AA, Minden A (2003) PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol Cell Biol 23:7122–7133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rosenberg D, Groussin L, Jullian E, Perlemoine K, Bertagna X, Bertherat J (2002) Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues. Ann N Y Acad Sci 968:65–74

    Article  CAS  PubMed  Google Scholar 

  27. Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7:737–749

    Article  CAS  PubMed  Google Scholar 

  28. Siu MK, Chan HY, Kong DS, Wong ES, Wong OG, Ngan HY, Tam KF, Zhang H, Li Z, Chan QK, Tsao SW, Strömblad S, Cheung AN (2010) p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients. Proc Natl Acad Sci USA 107:18622–18627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vaid M, Prasad R, Sun Q, Katiyar SK (2011) Silymarin targets β-catenin signaling in blocking migration/invasion of human melanoma cells. PLoS One 6:e23000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wells CM, Jones GE (2010) The emerging importance of group II PAKs. Biochem J 425:465–473

    Article  CAS  PubMed  Google Scholar 

  31. Yodkeeree S, Ampasavate C, Sung B, Aggarwal BB, Limtrakul P (2010) Demethoxycurcumin suppresses migration and invasion of MDA-MB-231 human breast cancer cell line. Eur J Pharmacol 627:8–15

    Article  CAS  PubMed  Google Scholar 

  32. Zhang HJ, Siu MK, Yeung MC, Jiang LL, Mak VC, Ngan HY, Wong OG, Zhang HQ, Cheung AN (2011) Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma. Carcinogenesis 32:765–771

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology of Korea (2010-0023292) and KRICT’s project, SI-1304, funded by the Ministry of Knowledge Economy, Republic of Korea.

Author information

Authors and Affiliations

  1. Department of Life Science, Gachon University, San 65, Bokjeong-Dong, Sujeong-Gu, Seongnam-Si, Gyeonggi-Do, 461-701, Korea

    Sang Yeol Lee

  2. Laboratory of Translational Therapeutics, Korea Research Institute of Chemical Technology, Yuseong-Gu, Taejon, 305-600, Korea

    Byung Jun Ryu, Sik-Won Choi & Seong Hwan Kim

  3. Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-Gu, Taejon, 305-600, Republic of Korea

    Hyuk Lee, Seong-Ho Kim & Jung-Nyoung Heo

  4. Research Institute of Basic Sciences, Sunchon National University, Suncheon, 540-742, Korea

    Jeong-Tae Yeon

  5. Division of Zoonoses, Korea Center for Disease Control & Prevention, Cheongwon County, Chungcheongbuk-Do, 363-951, Korea

    Jeongmin Lee

  6. Department of Dermatological Health Management, College of Health Science, Eulji University, Seongnam-Si, Gyeonggi-Do, 461-713, Korea

    Jongsung Lee

  7. Department of Genetic Engineering, Sungkyunkwan University, Suwon-Si, Gyeonggi-Do, 440-746, Korea

    Jae Youl Cho

Authors
  1. Byung Jun Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyuk Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seong-Ho Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jung-Nyoung Heo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sik-Won Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeong-Tae Yeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeongmin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jongsung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jae Youl Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Seong Hwan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sang Yeol Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Seong Hwan Kim or Sang Yeol Lee.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 4316 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ryu, B.J., Lee, H., Kim, SH. et al. PF-3758309, p21-activated kinase 4 inhibitor, suppresses migration and invasion of A549 human lung cancer cells via regulation of CREB, NF-κB, and β-catenin signalings. Mol Cell Biochem 389, 69–77 (2014). https://doi.org/10.1007/s11010-013-1928-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1928-8

Keywords

Search

Navigation