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Cellular, Molecular, and Tumor Biology 47: Analysis of p53-MDM2-ARF Pathways

Antitumor activity and bystander killing by p14ARF

Yinghui Huang, Per Borgstrom and Ruth A. Gjerset
Yinghui Huang
Sidney Kimmel Cancer Center, San Diego, CA
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Per Borgstrom
Sidney Kimmel Cancer Center, San Diego, CA
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Ruth A. Gjerset
Sidney Kimmel Cancer Center, San Diego, CA
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DOI:  Published April 2004
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Proc Amer Assoc Cancer Res, Volume 45, 2004

Abstract

2527

This study examined the antitumor effects and bystander killing associated with p14ARF (ARF) gene replacement. ARF is an important positive regulator of p53, but is absent in about 40% of cancers. Therapeutic strategies based on ARF could have potential for cancers retaining expression of wild-type p53, including up to 75% of breast cancers. We have used murine N202 breast cancer cells to examine the consequences of over expressing the N-terminal exon 1β-encoded region of ARF (ARF1β), the region that retains p53-dependent tumor suppressor activity. Treatment of N202 cells with a replication-defective adenovirus encoding ARF1β (denoted Ad1β) leads to the accumulation of p53, the induction of p53 target genes, and an elevation in the bax to bcl2 ratio, followed by apoptosis. Using a nude mouse dorsal skin fold chamber model to visualize the in vivo behavior of subcutaneous N202 tumor spheroids, we find that ARF1β abrogates tumorigenicity. In mixed spheroids composed of 25% or 50% ARF1β-modified cells plus unmodified bystander cells, we observe bystander cell apoptosis. Bystander apoptosis is vector independent and unrelated to angiogenesis, as it is observed prior to neovasculation. Consistent with these observations, we fail to observe differences in expression of vascular endothelial cells growth factor (VEGF) or thrombospondin-1, two genes that play positive and negative roles in vascularization, respectively, and that are regulated by p53 in some systems. Nevertheless, the bystander effect appears to be host-mediated, as it is not observed in vitro and cannot be transferred by culture supernatants of ARF1β–modified cells. The mechanism underlying these effects, together with other bystander mechanisms associated with p53 over expression could contribute to the success of ARF-based therapies, and other therapies that target the p53/ARF/mdm2 regulatory mechanism.

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April 2004
Volume 64, Issue 7 Supplement
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Antitumor activity and bystander killing by p14ARF
Yinghui Huang, Per Borgstrom and Ruth A. Gjerset
Cancer Res April 1 2004 (64) (7 Supplement) 584-585;

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Antitumor activity and bystander killing by p14ARF
Yinghui Huang, Per Borgstrom and Ruth A. Gjerset
Cancer Res April 1 2004 (64) (7 Supplement) 584-585;
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  • RAIG1 is a novel p53-regulated and growth-proliferative gene in human tumors
  • Identification of the interleukin-4 receptor alpha gene as a direct target for p73
  • Identification of the EDA receptor, EDAR and XEDAR, as a transcriptional target of p53
Show more Cellular, Molecular, and Tumor Biology 47: Analysis of p53-MDM2-ARF Pathways
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