Apoptotic death of hematopoietic tumor cells through potentiated and sustained adhesion to fibronectin via VLA-4.
It has been postulated that inactivated beta1-integrins are involved in the disordered growth of hematopoietic tumor cells. We recently found that TNIIIA2, a peptide derived from tenascin-C, strongly activates beta1-integrins through binding with syndecan-4. We show here that Ramos Burkitt's lymphoma cells can survive and grow in suspension but undergo apoptosis when kept adhering to fibronectin by stimulation with TNIIIA2. Other integrin activators, Mg(2+) and TS2/16 (an integrin-activating antibody), were also capable of inducing apoptosis. The inactivation of ERK1/2 and Akt and the subsequent activation of Bad were involved in the apoptosis. The results using other hematopoietic tumor cell lines expressing different levels of fibronectin receptors (VLA-4 and VLA-5) showed that potentiated and sustained adhesion to fibronectin via VLA-4 causally induces apoptosis also in various types of hematopoietic tumor cells in addition to Ramos cells. Because TNIIIA2 requires syndecan-4 as a membrane receptor for activation of beta1-integrins, it induced apoptosis preferentially in hematopoietic tumor cells, which expressed both VLA-4 and syndecan-4 as membrane receptors mediating the effects of fibronectin and TNIIIA2, respectively. Therefore, normal peripheral blood cells, such as neutrophils, monocytes, and lymphocytes, which poorly expressed syndecan-4, were almost insusceptible to TNIIIA2-induced apoptosis. The TNIIIA2-related matricryptic site of TN-C could contribute, once exposed, to preventing prolonged survival of hematopoietic malignant progenitors through potentiated and sustained activation of VLA-4.
Saito
Yohei
Y
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan.
Owaki
Toshiyuki
T
Matsunaga
Takuya
T
Saze
Mizue
M
Miura
Shogo
S
Maeda
Mao
M
Eguchi
Mayu
M
Tanaka
Rika
R
Taira
Junichi
J
Kodama
Hiroaki
H
Goto
Sumio
S
Niitsu
Yoshiroh
Y
Terada
Hiroshi
H
Fukai
Fumio
F
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002051:Burkitt Lymphoma; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D019337:Hematologic Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D005353:Fibronectins; D039041:Integrin alpha4beta1; D010455:Peptides; D053671:Syndecan-4; D019063:Tenascin; D051025:bcl-Associated Death Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases