A farnesyl-protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells Academic Article Article uri icon

Overview

MeSH Major

  • Antineoplastic Combined Chemotherapy Protocols
  • HSP90 Heat-Shock Proteins
  • Neoplasms
  • Proto-Oncogene Proteins

abstract

  • Farnesylation is required for the membrane partition and function of several proteins, including Ras. Farnesyl-protein transferase inhibitors (FTIs) were developed to prevent Ras processing and thus to be effective agents for the treatment of cancers harboring mutated ras. However, FTIs inhibit the growth of most tumor cells and several xenograft models, irrespective of whether they possess mutated ras. Furthermore, the antiproliferative effect is not correlated with inhibition of Ki-Ras processing; tumors with wild type ras are inhibited, and FTIs are not particularly toxic. These data suggest that the mechanism of FTI action is complex and may involve other targets besides Ras. To begin to understand how FTIs work, we investigated the mechanism of growth inhibition. FTI causes G1 arrest in a subset of sensitive lines. This is accomplished by transcriptional induction of p21, which mediates the inhibition of cyclin E-associated protein kinase activity, pRb hypophosphorylation and inhibition of DNA replication. Induction of p21 is p53-dependent; it does not occur in cells with mutant p53 or in cells expressing human papillomavirus E6. However, neither p53 nor p21 are required for inhibition of cell proliferation. FTI still blocks the growth of cells deficient in these proteins. In the absence of p21, G1 block is relaxed, DNA replication is not affected, and cells become polyploid and undergo apoptosis. These results suggest that farnesylated protein(s) may be involved in regulating p53 function and in coordinating entrance into S, and that the consequences of FTI treatment are a function of the other mutations found in the tumor cell.

publication date

  • August 7, 1998

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1074/jbc.273.32.20243

PubMed ID

  • 9685373

Additional Document Info

start page

  • 20243

end page

  • 51

volume

  • 273

number

  • 32