Induction of apoptosis in human neuroblastoma cells by abrogation of integrin‐mediated cell adhesion

The survival, proliferation and differentiation of neuroblastoma (NB) cells are largely dependent on adhesion to extra‐cellular matrix (ECM) proteins. Integrin occupancy seems to play a primary role. To elucidate the role of integrin heterodimers during neuronal cell death, we have analysed the changes in integrin expression in 2 human NB cell lines which represent different stages of neuronal maturation. Retinoic acid (RA) had different effects on the 2 NB cell lines: on LAN‐5 cells it acted as a differentiation‐promoting agent, while it had an anti‐proliferative effect on GI‐LI‐N cells, driving them driving them to apoptosis. Indeed, this occurrence was evidenced by the visualization of a “DNA ladder” on gel electrophoresis, by propidium iodine staining, and by DNA flow cytofluorimetric analysis. RA treatment rapidly and drastically decreased integrin expression and cell adhesion on GI‐LI‐N cells. These findings were also obtained by treating both NB cell lines with the apoptotic agent fenretinide. Furthermore, treatment of NB cells with anti‐sense oligonucleotides to β, integrin chain specifically induced chromatin condensation and nucleosomal DNA laddering. Moreover, blocking cell‐matrix interations by means of perturbing antibody against β, subunit resulted in the induction of typical features of apoptotic cells. In conclusion, these findings incidate that abrogation of cell adhesion through down‐modulation of integrin receptors plays a crucial role in the induction of neuroblastoma programmed cell death. Int. J. Cancer 70:688–698, 1997. © 1997 Wiley‐Liss, Inc.