A sychnological cell penetrating peptide mimic of p21 WAF1/CIP1 is pro-apoptogenic

Abstract

Targeting chemotherapeutic agents directly to sites of DNA replication and repair within cancerous cells is problematic. This study attempts to address the issue of nuclear delivery of biologically active peptides with the potential to disrupt cancer cell growth. Herein, the protein transduction domain of the HIV-1 transactivator of transcription, Tat (Tat 48–60), is used to deliver a cytotoxic peptide mimic of the cyclin-dependent kinase inhibitor, p21 WAF1/CIP1 into the nucleus. This construct, which we designate as Tat 48–60-P10, contains the PCNA interacting protein (PIP) box. We demonstrate the utility of Tat 48–60 for peptide delivery to the nucleus and show that Tat 48–60-P10 induces apoptosis specific to the inclusion of the wild type PIP box containing sequence. Colocalization of Tat 48–60-P10 with nuclear PCNA was observed by immunofluorescence analysis, supporting the hypothesis that cytotoxicity is potentially related to disruption of nuclear PCNA function. The U251 and U373 glioma cell lines exhibited particular sensitivity to the construct.