Apoptosis is being targeted to develop better therapies for colorectal cancer. We have found that (a) linoleic acid's product through 15-1ipoxygenase-1 (15-LOX-1), 13-S-hydroxyoctadecadienoic acid (13-S-HODE), restores apoptosis in colorectal cancer cells, (b) 13-S-HODE and 15-LOX-1 are downregulated in human colorectal cancer, and (c) NSAIDs restore 15-LOX-1 expression in human colorectal cancer cells to induce apoptosis and inhibit tumorigenesis. Human telomerase reverse transcriptase (hTERT) promoter can selectively express genes in cancer cells. The proposed research tests the following hypothesis: Selective restoration of 15-LOX-1 expression under the control of hTERT promoter in colorectal cancer cells via an adenoviral delivery system will reestablish apoptosis and inhibit tumorigenesis in colorectal cancer cells.
Specific Aims :
Aim 1 : To determine whether hTERT-driven 15-LOX-1 expression via an adenoviral vector reestablishes apoptosis through the expression of 15-LOX-1 in colorectal cancer cells, we will transfect colorectal cancer cell lines with an adenoviral vector (Ad-15-LOX-1) that expresses 15-LOX-1 under the control of the hTERT promoter and will measure 15-LOX-1 expression, 13-S-HODE levels, and apoptosis rates in vitro.
Aim 2 : To assess whether 15-LOX-1 expression driven by hTERT promoter through an adenoviral transfection system suppresses colorectal tumorigenesis in vivo, we will transfect Ad-15-LOX-1 by intratumoral injections into subcutaneous xenografts of human colorectal cancer cells in nude mice and assess the effects of 15-LOX-1 expression on tumorigenesis and apoptosis rates.
Aim 3 : To determine whether the systemic administration of hTERT-15-LOX-1 adenovirus selectively expresses 15-LOX-1 in tumor cells suppressing tumor growth, we will administer Ad-15-LOX-1 intravenously to nude mice carrying human colon cancer cell liver metastases and evaluate the 15-LOX-1 expression effects on tumor growth.
Aim 4 : To determine whether 15-LOX-1 downregulates Bcl-2 to induce apoptosis in colorectal cancer cells, we will examine (a) the effects of transfecting Ad-15-LOX-1 into colorectal cancer cells on Bcl-2 expression and (b) if overexpressing Bcl-2 inhibits 15-LOX-1 induced apoptosis. Confirming the feasibility of tumor selective targeting of 15-LOX-1 to inhibit tumorigenesis will pave the way for future preclinical and clinical development of therapeutic strategies based on molecularly targeting 15-LOX-1

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA104278-01A1
Application #
6823975
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Arya, Suresh
Project Start
2004-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$247,640
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Moussalli, Micheline J; Wu, Yuanqing; Zuo, Xiangsheng et al. (2011) Mechanistic contribution of ubiquitous 15-lipoxygenase-1 expression loss in cancer cells to terminal cell differentiation evasion. Cancer Prev Res (Phila) 4:1961-72
Zuo, X; Morris, J S; Broaddus, R et al. (2009) 15-LOX-1 transcription suppression through the NuRD complex in colon cancer cells. Oncogene 28:1496-505
Zuo, Xiangsheng; Peng, Zhanglong; Moussalli, Micheline J et al. (2009) Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis. J Natl Cancer Inst 101:762-7
Wu, Yuanqing; Fang, Bingliang; Yang, Xiulan Q et al. (2008) Therapeutic molecular targeting of 15-lipoxygenase-1 in colon cancer. Mol Ther 16:886-92
Zuo, Xiangsheng; Morris, Jeffrey S; Shureiqi, Imad (2008) Chromatin modification requirements for 15-lipoxygenase-1 transcriptional reactivation in colon cancer cells. J Biol Chem 283:31341-7
Zuo, X; Wu, Y; Morris, J S et al. (2006) Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene 25:1225-41