Expression of p16(INK4A) induces dominant suppression of glioblastoma growth in situ through necrosis and cell cycle arrest

Kuo Sheng Hung, Chi Yuan Hong, Jihjong Lee, Sze Kwan Lin, Shen C. Huang, Tong Mei Wang, Victor Tse, Gerald D. Sliverberg, Su Chuan Weng, Michael Hsiao

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Tumor suppressor genes may represent an important new therapeutic modality in the treatment of human glioblastoma (GBM). p16(INK4A) is a tumor suppressor gene with mutation and/or deletion found in many human tumors, including glioblastomas, melanoma, and leukemias. RT-2 rat GBM cell line was used to investigate if the p16 gene induces dominant suppression of glioblastoma growth. Close to 100% of tumor cells were infected by high titer pCL retrovirus encoding the full-length human p16 cDNA at 5 m.o.i. Infected cells showed a 98% reduction in colony forming assay and a 60% reduction in growth curves in vitro compared to vector control. Exogenous overexpression of p16 induced hypophosphorylation of Rb protein by Western blot analysis. Intracranial injection of p16-infected tumor cells into syngeneic rats resulted in a 95% reduction in tumor volume compared to the controls. Intratumoral injection of p16 retrovirus resulted in tumor necrosis and prominent human p16 transgene expressions. Proliferation marker PCNA was not detected in these human p16-expressed RT-2 tumor cells, suggesting the cells were unable to enter into S phase after p16 expression. In addition, direct repeat intracranial injections of p16 retrovirus prolonged animal survival 3.2-fold compared to the controls (48.4 ± 13.4 vs 15.0 ± 2.1 days, p <0.001). Two out of ten rats were found with dormant tumors at day 60 after p16 retrovirus injection. These results showed that p16 is effective in inhibiting GBM growth in situ. The mechanisms of tumor growth reduction and necrosis in vivo might be due to G1 arrest triggered by p16 expression. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)718-725
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume269
Issue number3
DOIs
Publication statusPublished - Mar 24 2000
Externally publishedYes

Keywords

  • Glioblastoma
  • p16
  • Retrovirus
  • Tumor suppression

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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