Abstract

Loss of p53-mediated apoptosis contributes to tumorigenesis and chemoresistance. We have used subtractive hybridization screening to isolate genes up-regulated early in the apoptotic process, following treatment of chemosensitive cells with adriamycin, using matched chemoresistant cells as a control. We isolate a novel gene, named KILLER/DR5, that is up-regulated in chemosensitive cells following exposure to adriamycin, etoposide or ionizing radiation. KILLER/DR5 is a member of the TNF cell death receptor family that activate the caspase cascade through interaction with cytoplasmic adaptors. KILLER/DR5 appears to be regulated by p53 and is an extremely potent suppressor of cancer cell growth through apoptosis induction. We propose to investigate the regulation of KILLER/DR5 gene expression, following DNA damaging radiation. We will investigate the structural requirements within KILLER/DR5, as well as it signaling mechanism for apoptosis. Our studies should lead to important knowledge about the mechanism of radiation induced apoptosis and further efforts directed at rational drug development for cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA075138-05
Application #
6616899
Study Section
Project Start
2002-07-22
Project End
2003-05-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
5
Fiscal Year
2002
Total Cost
$140,673
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Qayum, Naseer; Im, Jaehong; Stratford, Michael R et al. (2012) Modulation of the tumor microvasculature by phosphoinositide-3 kinase inhibition increases doxorubicin delivery in vivo. Clin Cancer Res 18:161-9
Higgins, Geoff S; Prevo, Remko; Lee, Yin-Fai et al. (2010) A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res 70:2984-93
Dorsey, Jay F; Mintz, Akiva; Tian, Xiaobing et al. (2009) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and paclitaxel have cooperative in vivo effects against glioblastoma multiforme cells. Mol Cancer Ther 8:3285-95
Hamilton, Julie; Grawenda, Anna M; Bernhard, Eric J (2009) Phosphatase inhibition and cell survival after DNA damage induced by radiation. Cancer Biol Ther 8:1577-86
Hamilton, Julie; Higgins, Geoff; Bernhard, Eric J (2009) Conventional radiotherapy or hypofractionation? A study of molecular changes resulting from different radiation fractionation schemes. Cancer Biol Ther 8:774-6
Qayum, Naseer; Muschel, Ruth J; Im, Jae Hong et al. (2009) Tumor vascular changes mediated by inhibition of oncogenic signaling. Cancer Res 69:6347-54
Al-Assar, Osama; Muschel, Ruth J; Mantoni, Tine S et al. (2009) Radiation response of cancer stem-like cells from established human cell lines after sorting for surface markers. Int J Radiat Oncol Biol Phys 75:1216-25
Lu, Chao; Wang, Wenge; El-Deiry, Wafik S (2008) Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73. Cancer Biol Ther 7:2039-46
Finnberg, Niklas; Klein-Szanto, Andres J P; El-Deiry, Wafik S (2008) TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J Clin Invest 118:111-23
Geiger, Geoffrey A; Fu, Weili; Kao, Gary D (2008) Temozolomide-mediated radiosensitization of human glioma cells in a zebrafish embryonic system. Cancer Res 68:3396-404

Showing the most recent 10 out of 98 publications