Skip to main content
Erschienen in: Digestive Diseases and Sciences 9/2007

01.09.2007 | Original Paper

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

Erschienen in: Digestive Diseases and Sciences | Ausgabe 9/2007

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat 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 6:3341–3351PubMed 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 6:3341–3351PubMed
2.
Zurück zum Zitat 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 63:213–224PubMedCrossRef 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 63:213–224PubMedCrossRef
3.
Zurück zum Zitat 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 63:167–174PubMedCrossRef 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 63:167–174PubMedCrossRef
4.
Zurück zum Zitat 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 63:225–233PubMedCrossRef 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 63:225–233PubMedCrossRef
5.
Zurück zum Zitat 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 10:4121–4128PubMed 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 10:4121–4128PubMed
6.
Zurück zum Zitat Ashman LK (1999) The biology of stem cell factor and its receptor c-kit. Int J Biochem 31:1037–1051 Ashman LK (1999) The biology of stem cell factor and its receptor c-kit. Int J Biochem 31:1037–1051
7.
Zurück zum Zitat 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 373:347–349CrossRef 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 373:347–349CrossRef
8.
Zurück zum Zitat 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 279:577–580PubMedCrossRef 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 279:577–580PubMedCrossRef
9.
Zurück zum Zitat 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 33:1182–1187PubMedCrossRef 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 33:1182–1187PubMedCrossRef
10.
Zurück zum Zitat 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 91:661–663PubMed 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 91:661–663PubMed
11.
Zurück zum Zitat 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 92:1736–1744PubMedCrossRef 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 92:1736–1744PubMedCrossRef
12.
Zurück zum Zitat 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 10:3076–3081PubMedCrossRef 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 10:3076–3081PubMedCrossRef
13.
Zurück zum Zitat Karin M (1992) Signal transduction form cell surface to nucleus in development and disease. FASEB J 6:2581–2590PubMed Karin M (1992) Signal transduction form cell surface to nucleus in development and disease. FASEB J 6:2581–2590PubMed
14.
Zurück zum Zitat Levitzki A, Gazit A (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788PubMedCrossRef Levitzki A, Gazit A (1995) Tyrosine kinase inhibition: an approach to drug development. Science 267:1782–1788PubMedCrossRef
15.
Zurück zum Zitat Heinrich MC, Rubin BP, Longley BJ, Fletcher JA (2002) Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 33:484–495PubMedCrossRef Heinrich MC, Rubin BP, Longley BJ, Fletcher JA (2002) Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 33:484–495PubMedCrossRef
16.
Zurück zum Zitat Roskoski R Jr (2005) Structure and regulation of Kit protein-tyrosine kinase-The stem cell factor receptor. Biochem Biophys Res Commun 338:1307–1315PubMedCrossRef Roskoski R Jr (2005) Structure and regulation of Kit protein-tyrosine kinase-The stem cell factor receptor. Biochem Biophys Res Commun 338:1307–1315PubMedCrossRef
17.
Zurück zum Zitat 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:S19–27PubMedCrossRef 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:S19–27PubMedCrossRef
18.
Zurück zum Zitat 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 14:295–302PubMedCrossRef 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 14:295–302PubMedCrossRef
19.
Zurück zum Zitat 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 172:1–11PubMedCrossRef 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 172:1–11PubMedCrossRef
20.
Zurück zum Zitat 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 19:545–553PubMedCrossRef 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 19:545–553PubMedCrossRef
21.
Zurück zum Zitat 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 61:2200–2206PubMed 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 61:2200–2206PubMed
22.
Zurück zum Zitat 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 3:385–392PubMed 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 3:385–392PubMed
23.
Zurück zum Zitat 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 62:4879–4883PubMed 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 62:4879–4883PubMed
24.
Zurück zum Zitat 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 81:656–660PubMed 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 81:656–660PubMed
25.
Zurück zum Zitat Kitoh T, Ishikawa H, Ishii T, Nakagawa S (1998) Elevated SCF levels in the serum of patients with chronic renal failure. Br J Haematol 102:1151–1156PubMedCrossRef Kitoh T, Ishikawa H, Ishii T, Nakagawa S (1998) Elevated SCF levels in the serum of patients with chronic renal failure. Br J Haematol 102:1151–1156PubMedCrossRef
26.
Zurück zum Zitat Kitamura Y, Hirota S (2004) Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 61:2924–2931PubMedCrossRef Kitamura Y, Hirota S (2004) Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci 61:2924–2931PubMedCrossRef
27.
Zurück zum Zitat 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 2:32PubMedCrossRef 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 2:32PubMedCrossRef
28.
Zurück zum Zitat Wang WS, Chen PM, Su Y (2006) Colorectal carcinoma: from tumorigenesis to treatment. Cell Mol Life Sci 63:663–671PubMedCrossRef Wang WS, Chen PM, Su Y (2006) Colorectal carcinoma: from tumorigenesis to treatment. Cell Mol Life Sci 63:663–671PubMedCrossRef
29.
Zurück zum Zitat Wong SF (2005) Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther 27:684–694PubMedCrossRef Wong SF (2005) Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin Ther 27:684–694PubMedCrossRef
30.
Zurück zum Zitat Whisenant J, Bergsland E (2005) Anti-angiogenic strategies in gastrointestinal malignancies. Curr Treat Options Oncol 6:411–421PubMedCrossRef Whisenant J, Bergsland E (2005) Anti-angiogenic strategies in gastrointestinal malignancies. Curr Treat Options Oncol 6:411–421PubMedCrossRef
Metadaten
Titel
Stem Cell Factor/c-kit Receptor Signaling Enhances the Proliferation and Invasion of Colorectal Cancer Cells Through the PI3K/Akt Pathway
Publikationsdatum
01.09.2007
Erschienen in
Digestive Diseases and Sciences / Ausgabe 9/2007
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-007-9759-7

Weitere Artikel der Ausgabe 9/2007

Digestive Diseases and Sciences 9/2007 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.