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Address: Arizona Cancer Center 3999B
PO Box 245024

Tucson, AZ 85724-5044
Phone: 520-626-8044
E-Mail: nignatenko@azcc.arizona.edu

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Research Interests

A major focus of my research is on study of molecular changes in gaA 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. strointestinal tract leading to malignancy for the purpose of identification of molecular markers for detection or prevention of gastrointestinal cancer.

Selected Publications

Roy UK, Henkhaus RS, Ignatenko NA, Mora J, Fultz KE, Gerner EW. Apr 2008. Wild-type APC regulates caveolin-1 expression in human colon adenocarcinoma cell lines via FOXO1a and C-myc. Mol Carcinog,2008 Apr 28;

Henkhaus RS, Roy UK, Cavallo-Medved D, Sloane BF, Gerner EW, Ignatenko NA. Feb 2008. Caveolin-1-mediated expression and secretion of kallikrein 6 in colon cancer cells. Neoplasia, 10:140-8

Hariri LP, Qiu Z, Tumlinson AR, Besselsen DG, Gerner EW, Ignatenko NA, Povazay B, Hermann B, Sattmann H, McNally J, Unterhuber A, Drexler W, Barton JK. Aug 2007. Serial endoschop in azoxymethane treated mice using ultra-high resolution optical coherence tomography. Cancer Biology and Therapy, 6:1753-62

Bernstein H, Holubec H, Bernstein C, Ignatenko NA, Gerner E, Dvorak K, Besselsen D, Blohm-Mangone KA, Padilla-Torres J, Dvorakova B, Garewal H, Payne CM. Mar 2007. Deoxycholate-induced colitis is markedly attenuated in Nos2 knockout mice in association with modulation of gene expression profiles. Dig Dis Sci, 52:628-42