Skip to main content

Advertisement

SpringerLink
Log in

Stem Cell Factor/c-kit Receptor Signaling Enhances the Proliferation and Invasion of Colorectal Cancer Cells Through the PI3K/Akt Pathway

  • Original Paper
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

In this study, we examined the role of c-kit receptor (KIT) signal transduction on the proliferation and invasion of colorectal cancer cells. We found that c-kit was expressed in 2 colorectal cancer cell lines as determined by RT-PCR, Western blot, and flow cytometry. In KIT-positive lines, KIT was activated by stem cell factor (SCF). SCF enhanced cellular proliferation of positive lines as demonstrated by the WST-1 proliferation assay. Furthermore, SCF enhanced the invasive ability of KIT-positive cell lines. SCF stimulation upregulated p44/42 mitogen-activated protein kinase (MAPK) and Akt as shown by Western blot. We examined the roles played by p44/42 MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways in proliferation and invasion. PI3K/Akt activity strongly correlated with proliferation and invasion and p44/42 MAPK was correlated with only invasion. In conclusion, the SCF-enhanced proliferation and invasion of KIT-positive colorectal cancer cells is achieved mainly through the PI3K/Akt pathway.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A (1987) Human proto-oncogene c-kit: a new surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6:3341–3351

    PubMed  CAS  Google Scholar 

  2. Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Mrdock DC, Jacobsen FW, Langley KE, Smith KA, Takeishi T, Cattanach BM, Galli SJ, Suggs SV (1990) Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63:213–224

    Article  PubMed  CAS  Google Scholar 

  3. Williams DE, Eisenman J, Baird A, Rauch C, Ness KV, March CJ, Park LS, Martin U, Mochizuki DY, Boswell HS, Burgess GS, Cosman D, Lyman SD (1990) Identification of a ligand for the c-kit proto-oncogene. Cell 63:167–174

    Article  PubMed  CAS  Google Scholar 

  4. Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, Wellner D, Leder P, Besmer P (1990) The hematopoietic growth factor KL is encoded by the SI locus and is the ligand of c-kit receptor, the gene product of the W locus. Cell 63:225–233

    Article  PubMed  CAS  Google Scholar 

  5. Blume-Jensen P, Claesson-Welsh L, Siegbahn A, Zsebo KM, Westermark B, Helden CH (1991) Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J 10:4121–4128

    PubMed  CAS  Google Scholar 

  6. Ashman LK (1999) The biology of stem cell factor and its receptor c-kit. Int J Biochem 31:1037–1051

    CAS  Google Scholar 

  7. Hulzinga JD, Thuneberg L, Klüpel M, Malysz J, Mikkelsen HB, Bernstein A (1985) W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373:347–349

    Article  Google Scholar 

  8. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurarta A, Takeda M, Muhammad T, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580

    Article  PubMed  CAS  Google Scholar 

  9. Naeem M, Dahiya M, Clark JI, Clark JI, Creech SD, Alkan S (2002) Analysis of c-kit protein expression in small-cell lung carcinoma and its implication for prognosis. Hum Pathol 33:1182–1187

    Article  PubMed  CAS  Google Scholar 

  10. Nakata Y, Kimura A, Katoh O, Kawaishi K, Hyodo H, Abe K, Kuramoto A, Satow Y (1995) c-kit point mutation of extracellular domain in patients with myeloproliferative disorders. Br J Haematol 91:661–663

    PubMed  CAS  Google Scholar 

  11. Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugihara H, Butterfield JH, Ashman LK, Kanayama Y, Matsuzawa Y, Kitamura Y, Kanakura Y (1993) Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest 92:1736–1744

    Article  PubMed  CAS  Google Scholar 

  12. Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, Kim JS, Yook JH, Kim BS, Lee JS (2004) Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors. Clin Cancer Res 10:3076–3081

    Article  PubMed  CAS  Google Scholar 

  13. Karin M (1992) Signal transduction form cell surface to nucleus in development and disease. FASEB J 6:2581–2590

    PubMed  CAS  Google Scholar 

  14. Levitzki A, Gazit A (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788

    Article  PubMed  CAS  Google Scholar 

  15. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA (2002) Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 33:484–495

    Article  PubMed  CAS  Google Scholar 

  16. Roskoski R Jr (2005) Structure and regulation of Kit protein-tyrosine kinase-The stem cell factor receptor. Biochem Biophys Res Commun 338:1307–1315

    Article  PubMed  CAS  Google Scholar 

  17. Manley PW, Cowan-Jacob SW, Buchdunger E, Fabbro D, Fendrich G, Furet P, Meyrer T, Zimmermann J (2002) Imatinib: a selective tyrosine kinase inhibitor. Eur J Cancer 38 Suppl 5:S19–27

    Article  PubMed  Google Scholar 

  18. Toyota M, Hinoda Y, Takaoka A, Makiguchi Y, Takahashi T, Itoh F, Imai K, Yachi A (1993) Expression of c-kit and kit Ligand in Human Colon Carcinoma Cells. Tumour Biol 14:295–302

    Article  PubMed  CAS  Google Scholar 

  19. Bellone G, Silvestri S, Artusio E, Tibaudi D, Turletti A, Geuna M, Giachino C, Valente G, Emanuelli G, Rodeck U (1997) Growth stimulation of colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-β1. J Cell Physiol 172:1–11

    Article  PubMed  CAS  Google Scholar 

  20. Sammarco I, Capurso G, Coppola L, Bonifazi AP, Cassetta S, Fave GD, Carrara A, Grassi GB, Rossi P, Sette C, Geremmia R (2004) Expression of the proto-oncogene c-kit in normal and tumor tissues from colorectal carcinoma patients. Int J Colorectal Dis 19:545–553

    Article  PubMed  Google Scholar 

  21. Bellone G, Carbone A, Sibona N, Bosco O, Tibaudi D, Smirne C, Martone T, Gramigni C, Camandona M, Emanuelli G, Rodeck U (2001) Aberrant activation of c-kit protects colon carcinoma cells against apoptosis and enhances their invasive potential. Cancer Res 61:2200–2206

    PubMed  CAS  Google Scholar 

  22. Bellone G, Ferrero D, Carbone A, De Quadros MR, Gramigni C, Prati A, Davidson W, Mioli P, Dughera L, Emanuelli G, Rodeck U (2004) Inhibition of cell survival and invasive potential of colorectal carcinoma cells by the tyrosine kinase inhibitor STI571. Cancer Biol Ther 3:385–392

    PubMed  CAS  Google Scholar 

  23. Attoub S, Rivat C, Rodrigues S, Van Bocxlaer S, Bedin M, Bruyneel E, Louvet C, Kornprobst M, Andre T, Mareel M, Mester J, Gespach C (2002) The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. Cancer Res 62:4879–4883

    PubMed  CAS  Google Scholar 

  24. Langley KE, Bennett LG, Wypych J, Yancik SA, Liu XD, Westcott KR, Chang DG, Smith KA, Zsebo KM (1993) Soluble stem cell factor in human serum. Blood 81:656–660

    PubMed  CAS  Google Scholar 

  25. Kitoh T, Ishikawa H, Ishii T, Nakagawa S (1998) Elevated SCF levels in the serum of patients with chronic renal failure. Br J Haematol 102:1151–1156

    Article  PubMed  CAS  Google Scholar 

  26. Kitamura Y, Hirota S (2004) Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 61:2924–2931

    Article  PubMed  CAS  Google Scholar 

  27. Li J, Kleeff J, Guo J, Fischer L, Giese N, Buchler MW, Friess H (2003) Effects of STI571 (gleevec) on pancreatic cancer cell growth. Mol Cancer 2:32

    Article  PubMed  Google Scholar 

  28. Wang WS, Chen PM, Su Y (2006) Colorectal carcinoma: from tumorigenesis to treatment. Cell Mol Life Sci 63:663–671

    Article  PubMed  CAS  Google Scholar 

  29. Wong SF (2005) Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther 27:684–694

    Article  PubMed  CAS  Google Scholar 

  30. Whisenant J, Bergsland E (2005) Anti-angiogenic strategies in gastrointestinal malignancies. Curr Treat Options Oncol 6:411–421

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya, 4678601, Japan

    Akira Yasuda, Hirozumi Sawai, Hiroki Takahashi, Nobuo Ochi, Yoichi Matsuo, Hitoshi Funahashi, Mikinori Sato, Yuji Okada, Hiromitsu Takeyama & Tadao Manabe

Authors
  1. Akira Yasuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hirozumi Sawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuo Ochi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoichi Matsuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hitoshi Funahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mikinori Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuji Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiromitsu Takeyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tadao Manabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akira Yasuda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yasuda, A., Sawai, H., Takahashi, H. et al. Stem Cell Factor/c-kit Receptor Signaling Enhances the Proliferation and Invasion of Colorectal Cancer Cells Through the PI3K/Akt Pathway. Dig Dis Sci 52, 2292–2300 (2007). https://doi.org/10.1007/s10620-007-9759-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-007-9759-7

Keywords

Search

Navigation