Tumor suppression and inhibition of aneuploid cell accumulation in human brain tumor cells by ectopic overexpression of the cyclin-dependent kinase inhibitor p27(KIP1)

To investigate how overexpression of p27(KIP1), a downstream effector of TGF-beta and a universal cyclin-dependent kinase (CDK) inhibitor could influence the malignant phenotype of malignant human brain tumor cells, an adenovirus vector system was used to transfer the human p27(KIP1) gene (Adp27(KIP1)) into the human astrocytoma cell line, U-373MG. Inhibition of CDK activity in Adp27(KIP1)-infected cells was indicated by inhibition of [H-3]thymidine incorporation, an increase in cell doubling time and by cell cycle arrest in G(1). Notably, ectopic overexpression of p27(KIP1) was associated with a marked decrease in the accumulation of aneuploid cells. Diminished malignant potential of Adp27(KIP1)-infected cells was manifested by the loss of anchorage-independent growth in soft agar and by the inability to induce tumorgenesis in a xenograft model. These studies suggest that p27(KIP1) is a tumor suppressor gene and supports the use of Adp27(KIP1) for gene therapy of human brain tumors.