Inhibition of Both Mesothelioma Cell Growth and Cdk4 Activity following Treatment with a TATp16^INK4a Peptide

Abstract

Disruption of the 9p21 locus is common in mesothelioma and leads to loss of both the p16^INK4a and the p14^ARF gene products. This study tested the hypothesis that re-expression of p16^INK4a carried out using the TAT delivery system that carries the protein transduction domain of the HIV TAT will result in mesothelioma cell death. Materials and Methods: A synthetic TATp16^INK4a peptide and a charge matched control were transduced into mesothelioma cells in vitro and in vivo. Cells were assayed for Cdk4 inhibition, cell cycle arrest, and cell death. Results: Treatment of mesothelioma cells with TATp16^INK4a for 48 hours resulted in cell death. Apoptosis and G₁ cell cycle arrest was also observed. Following transduction of cells with TATp16^INK4a there was complete but transient hypophosphorylation of pRb. Similar effects were observed in mesothelioma xenografts. Conclusion: Therapeutic strategies which introduce either TATp16^INK4a peptide, or small molecule mimetic, could be an effective strategy for mesothelioma treatment.