Natalia Ignatenko
Research Assistant Professor
Department of Cell Biology and Anatomy
Arizona Cancer Center 3999B
e-mail: nignatenko@azcc.arizona.edu; nai@email.arizona.edu
Phone: (520) 626-8044
Research Interest:
A major focus of my research is on study of molecular changes in gastrointestinal tract leading to malignancy for the purpose of identification of molecular markers for detection or prevention of gastrointestinal cancer. My research efforts have been concentrated on the following areas:
1) Identification of effects of mutations in the tumor suppressor gene Adenomatous
Polyposis Coli (APC) on biochemical and molecular aspects of polyamine metabolism.
The polyamines, spermidine, spermine and diamine putrescine, are polications, essential for optimal growth. Using the Min (multiple intestinal neoplasia) mice as a model of human autosomal dominantly inherited syndrome of familial adenomatous polyposis (FAP) we found the APC-mediated transcriptional activation of the key polyamine biosynthetic enzyme ornithine decarboxylase (ODC). Treatment of Min mice, having the mutation in the APC gene, with sulindac, the non-steroidal anti-inflammatory drug (NSAID), alone, or in combination with the ODC inhibitor a–difluoromethylornithine (DFMO) decreases the intestinal and colonic tumor formation. Treatment with sulindac and its metabolite sulindac sulfone results in increase in steady state levels of spermidine/spermine N1-acetyltransferase SSAT RNA in Min mouse model.
2) Study of the consequences of mutation in the K-ras protooncogene in colon cancer.
We have shown the decrease in the steady state RNA levels of the rate-limiting polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) in colon cancer cell lines with mutant K-ras oncogene. Sulindac sulfone induces the SSAT promoter in the colon adenocarcinoma cells Caco-2, suggesting that molecular mechanisms of anticancer action of NSAIDs include their effect on polyamine metabolism. SSAT suppression occurs via a mechanism involving MEK-dependent down regulation of peroxisome proliferator-activated reseptor gamma (PPARg).
3) Investigate the genetic interactions of oncogenic K-ras gene and innactivated p53 tumor suppressor gene in development of invasive phenotype of colon and pancreatic adenocarcinomas. We have shown that expression of an activated K-ras Val12 is sufficient to convey a tumorigenic phenotype to human Caco-2 colon cancer cells. Transcriptional targets related to the invasive phenotype of colon cancer cells have been identified using the cDNA microarray analysis. Genes up-regulated by an activated K-ras include cell cell communication genes, such as cytoskeletal-, transport-, protease-, and gap junction-associated proteins. Genes identified in this study are now under evaluation as a potential new molecular targets for pharmaceutical interventions.
Selected Publications:
Gerner EW, Ignatenko NA, Besselsen DE (2003) Preclinical models for chemoprevention of colon cancer. Recent Results in Cancer Research 163, 58-71.
Ignatenko NA and Gerner EW (2003) Regulation of the HIV1 long terminal repeat by mutant heat shock factor. Experimental Cell Research 288, 1-8.
Qu N, Ignatenko NA, Yamuchi P, Gerner EW (2003) Stereospecific inhibition of human ornithine decarboxylase activity by enantiomers of difluoromethylornithine. Biochemical Journal 275, 465-470.
Babbar N, Ignatenko NA, Casero RA, and Gerner EW. (2003) Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. Journal of Biological Chemistry 278, 47762-4775.
Ignatenko NA. Babbar N, Mehta D, Casero R.A, Gerner EW. (2004) Suppression of polyamine catabolism by activated K-ras in human colon cell lines. Molecular Carcinogenesis 39:91-102.
Ignatenko NA, Zhang H., Watts GS, Skovan BA, Stringer DE, Gerner EW. (2004) The chemopreventive agent a-difluoromethylornithine blocks K-ras dependent tumor formation and specific gene expression in Caco-2 cells. Molecular Carcinogenesis 39:221-233.
