APOPTOSIS IN COLON CANCER CHEMOPREVENTION

Summary

Principal Investigator: E W Gerner
Abstract: APPLICANT'S DESCRIPTION Colon cancer remains the second leading cause of cancer death in the United States of America, affecting both males and females. The major theme of this program is the study of apoptosis in colon carcinogenesis and colon cancer chemoprevention. Studies in experimental rodent models and humans indicate that genetic and intestinal luminal risk factors decrease cell turnover, in part by decreasing apoptosis, in normal and neoplastic colonic tissues. Intestinal luminal risk factors include the secondary bile acids, which are affected by both genetic and dietary factors. Our program addresses both genetic and intestinal luminal risk factors, as we hypothesize that common signaling and metabolic pathways downstream of both these factors mediate cell turnover in colonic tissues and, subsequently, colon cancer risk. A corollary of this hypothesis is that these downstream pathways are rational targets for colon cancer chemoprevention strategies in humans. To test this hypothesis, we have designed projects and cores that are interactive and complementary. One project studies biochemical effectors of genes, including the Ki-ras oncogene and the APC and p53 tumor suppressor genes, which are frequently mutated in human colon cancers. A second project focuses on the role of nitric oxide in bile acid induced apoptosis. The third project emphasizes studies of the AP-1 transcription factor, which is involved in signaling pathways mediated by both APC and bile acids. The specific aims of the projects are to determine the roles of genetic and intestinal luminal risk factors in cell turnover in colonic tissues, to describe mechanisms underlying these processes, and to investigate the consequences of specific pharmacological and/or dietary interventions on cell turnover and colon carcinogenesis. The projects will address these aims using genetically altered cell culture and rodent models of colon cancer, and a variety of biochemical, molecular and cellular biology technologies. Four cores provide support in cell and tissue pathology, breeding and maintaining genetically altered rodent models of colon carcinogenesis, biometry and administration and evaluation. The long-term goal of the Apoptosis in Colon Cancer Chemoprevention Program Project Grant is to understand mechanisms of colon carcinogenesis in humans and then to use this information to establish the rational for strategies of colon cancer prevention and/or treatment.
Funding Period: 1997-07-01 - 2005-12-31
more information: NIH RePORT

Top Publications

  1. pmc Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas
    K P Raj
    Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA
    Br J Cancer 108:512-8. 2013
  2. pmc Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer
    Nathaniel S Rial
    Department of Internal Medicine, The University of Arizona Medical Center, PO Box 245040, 1501 N Campbell Avenue, Tucson, AZ 85724, USA
    Expert Rev Gastroenterol Hepatol 6:507-17. 2012
  3. pmc DFMO: targeted risk reduction therapy for colorectal neoplasia
    Christina M Laukaitis
    Department of Medicine, University of Arizona, 1515 N Campbell Ave, Tucson, AZ 85724, USA
    Best Pract Res Clin Gastroenterol 25:495-506. 2011
  4. pmc Regulation of deoxycholate induction of CXCL8 by the adenomatous polyposis coli gene in colorectal cancer
    Nathaniel S Rial
    Cancer Biology Graduate Interdisciplinary Program, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
    Int J Cancer 124:2270-80. 2009
  5. pmc Components of metabolic syndrome and metachronous colorectal neoplasia
    Erin L Ashbeck
    Arizona Cancer Center, Tucson, AZ 85724, USA
    Cancer Epidemiol Biomarkers Prev 18:1134-43. 2009
  6. pmc Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis
    Upal K Basu Roy
    Biochemistry and Molecular and Cellular Biology Graduate Program, University of Arizona, Tucson, Arizona, USA
    Mol Carcinog 47:538-53. 2008
  7. pmc Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis
    Natalia A Ignatenko
    Department of Cell Biology and Anatomy, Arizona Cancer Center, The University of Arizona, Tucson, USA
    Nutr Cancer 56:172-81. 2006
  8. ncbi Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention
    E W Gerner
    Arizona Cancer Center, Department of Cell Biology and Anatomy, The University of Arizona, Tucson, AZ 85724, USA
    Amino Acids 33:189-95. 2007
  9. ncbi Profiling of selenomethionine responsive genes in colon cancer by microarray analysis
    Anne Christine Goulet
    Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA
    Cancer Biol Ther 6:494-503. 2007
  10. ncbi Deoxycholate-induced colitis is markedly attenuated in Nos2 knockout mice in association with modulation of gene expression profiles
    Harris Bernstein
    Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona 85724 5044, USA
    Dig Dis Sci 52:628-42. 2007

Scientific Experts

  • J A Zell
  • Claire Margaret Payne
  • Carol Bernstein
  • Natalia A Ignatenko
  • Frank Meyskens
  • Naveen Babbar
  • Ashley A Powell
  • Eugene W Gerner
  • Harris Bernstein
  • Hana Holubec
  • Harinder Garewal
  • Nathaniel S Rial
  • Sandeep Akare
  • Hagit F Yerushalmi
  • Jesse D Martinez
  • Upal K Basu Roy
  • Katerina Dvorak
  • Anne Christine Goulet
  • Lois Ramsey
  • Katerina Dvorakova
  • David E Stringer
  • Samira Jean-Louis
  • Monique Dall'Agnol
  • Anil Prasad
  • H Bernstein
  • K P Raj
  • Christina M Laukaitis
  • Peter Lance
  • Rebecca Feldman
  • Erin L Ashbeck
  • Takeshi Uemura
  • Karen Ann Blohm-Mangone
  • Jose Padilla-Torres
  • David Besselsen
  • Haiyan Cui
  • K Dvorak
  • Karen A Blohm-Mangone
  • Mark A Nelson
  • Jose L Padilla-Torres
  • David G Besselsen
  • H Garewal
  • James A Warneke
  • Eunok Im
  • C L Rock
  • C Zoumas-Morse
  • C E McLaren
  • Alfred M Cohen
  • Anil R Prasad
  • Robert S Krouse
  • Gwendal Lazennec
  • Elizabeth T Jacobs
  • Patricia A Thompson
  • Maria Elena Martinez
  • Leo Hawel
  • Kirk E Pastorian
  • Karen L Kachel
  • George Tsaprailis
  • Kimberly E Fultz
  • Rebecca S Henkhaus
  • Craig V Byus
  • Jessica Mora
  • George Watts
  • Barbora Dvorakova
  • Jean L Lord
  • Emmanuelle Meuillet
  • B Dvorakova
  • Wemin Chen
  • M Chavarria
  • Richard Sampliner
  • M Ahad Ali
  • R Fass
  • R Dekel
  • Daniel J Wood
  • Eugene A Mash
  • Megan Wilson
  • Ronnie Fass
  • Jose M Guillen
  • K Dvorakova
  • Marianne Chigbrow
  • Melissa Chavarria
  • Peter Frisk
  • Chris Riley
  • Richard E Sampliner
  • Caroline N Waltmire

Detail Information

Publications40

  1. pmc Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas
    K P Raj
    Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA
    Br J Cancer 108:512-8. 2013
    ..Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial...
  2. pmc Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer
    Nathaniel S Rial
    Department of Internal Medicine, The University of Arizona Medical Center, PO Box 245040, 1501 N Campbell Avenue, Tucson, AZ 85724, USA
    Expert Rev Gastroenterol Hepatol 6:507-17. 2012
    ..It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors...
  3. pmc DFMO: targeted risk reduction therapy for colorectal neoplasia
    Christina M Laukaitis
    Department of Medicine, University of Arizona, 1515 N Campbell Ave, Tucson, AZ 85724, USA
    Best Pract Res Clin Gastroenterol 25:495-506. 2011
    ..Targeting this therapy to people at elevated risk of CRC, and employing clinical and genetic predictors, should improve patient benefit and reduce the risk of side effects to improve the acceptability of this strategy...
  4. pmc Regulation of deoxycholate induction of CXCL8 by the adenomatous polyposis coli gene in colorectal cancer
    Nathaniel S Rial
    Cancer Biology Graduate Interdisciplinary Program, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
    Int J Cancer 124:2270-80. 2009
    ..These data suggest that DCA-mediated CXCL8 occurs in initiated colonic epithelium and neutralizing CXCL8 could reduce the invasive potential of tumors...
  5. pmc Components of metabolic syndrome and metachronous colorectal neoplasia
    Erin L Ashbeck
    Arizona Cancer Center, Tucson, AZ 85724, USA
    Cancer Epidemiol Biomarkers Prev 18:1134-43. 2009
    ..The consistent association between obesity and colorectal cancer is thought to be explained by metabolic disturbances common, but not exclusive, to the obese...
  6. pmc Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis
    Upal K Basu Roy
    Biochemistry and Molecular and Cellular Biology Graduate Program, University of Arizona, Tucson, Arizona, USA
    Mol Carcinog 47:538-53. 2008
    ..These data indicate that polyamine transport follows a dynamin-dependent and clathrin-independent endocytic uptake route, and this route is positively regulated by the oncogenic expression of K-RAS in a caveolin-1 dependent manner...
  7. pmc Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis
    Natalia A Ignatenko
    Department of Cell Biology and Anatomy, Arizona Cancer Center, The University of Arizona, Tucson, USA
    Nutr Cancer 56:172-81. 2006
    ..Because high concentrations of putrescine can be found in certain dietary components, it may be advantageous to restrict dietary putrescine consumption in patients undergoing treatment with sulindac...
  8. ncbi Rationale for, and design of, a clinical trial targeting polyamine metabolism for colon cancer chemoprevention
    E W Gerner
    Arizona Cancer Center, Department of Cell Biology and Anatomy, The University of Arizona, Tucson, AZ 85724, USA
    Amino Acids 33:189-95. 2007
    ..Seventy percent of participants will have completed the three years of treatment in December 2006...
  9. ncbi Profiling of selenomethionine responsive genes in colon cancer by microarray analysis
    Anne Christine Goulet
    Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA
    Cancer Biol Ther 6:494-503. 2007
    ..Finally, our studies provide a practical foundation for the further development of biomarkers to monitor the efficacy of selenomethionine in clinical trials...
  10. ncbi Deoxycholate-induced colitis is markedly attenuated in Nos2 knockout mice in association with modulation of gene expression profiles
    Harris Bernstein
    Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, Arizona 85724 5044, USA
    Dig Dis Sci 52:628-42. 2007
    ..Overall, our results indicate that NOS2 expression is necessary for the development of deoxycholate-induced colitis in mice, a unique dietary-related model of colitis...
  11. pmc Abnormal expression of biomarkers in incompletely ablated Barrett's esophagus
    Katerina Dvorak
    Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ, USA
    Ann Surg 244:1031-6. 2006
    ....
  12. ncbi Wild-type APC regulates caveolin-1 expression in human colon adenocarcinoma cell lines via FOXO1a and C-myc
    Upal K Basu Roy
    Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA
    Mol Carcinog 47:947-55. 2008
    ..Our results would be consistent with the interpretation that caveolin-1 may have tumor suppressing functions during early stages of colon carcinogenesis...
  13. pmc Identification and characterization of a diamine exporter in colon epithelial cells
    Takeshi Uemura
    Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA
    J Biol Chem 283:26428-35. 2008
    ..The interaction between SLC3A2 and SAT1 suggests that these proteins may facilitate excretion of acetylated polyamines...
  14. pmc Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial
    Frank L Meyskens
    Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA
    Cancer Prev Res (Phila) 1:32-8. 2008
    ..Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects...
  15. ncbi Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis
    Natalia A Ignatenko
    The University of Arizona, Arizona Cancer Center, 1515 N Campbell Avenue, Tucson, AZ 85724, USA
    Nutr Cancer 60:30-5. 2008
    ....
  16. pmc Combination chemoprevention for colon cancer targeting polyamine synthesis and inflammation
    Eugene W Gerner
    The University of Arizona, Arizona Cancer Center, Tucson, Arizona 85724, USA
    Clin Cancer Res 15:758-61. 2009
    ....
  17. pmc Risk of cardiovascular events in a randomized placebo-controlled, double-blind trial of difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas
    Jason A Zell
    Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA
    Cancer Prev Res (Phila) 2:209-12. 2009
    ..These results have implications for future NSAID-based cancer prevention clinical trials...
  18. pmc Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR
    Rebecca Feldman
    Cancer Biology Graduate Program, University of Arizona, Tucson, AZ 85724, USA
    Biochim Biophys Acta 1793:1387-94. 2009
    ..Taken together these results suggest that UDCA may act to suppress cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation...
  19. pmc Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival
    Jason A Zell
    Department of Epidemiology, University of California, Irvine, California 92697, USA
    Clin Cancer Res 15:6208-16. 2009
    ..We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer-specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells...
  20. ncbi Role of c-Myc in intestinal tumorigenesis of the ApcMin/+ mouse
    Natalia A Ignatenko
    Department of Cell Biology and Anatomy, The University of Arizona, Tucson, Arizona 85724, USA
    Cancer Biol Ther 5:1658-64. 2006
    ..Thus, conditional inactivation of c-Myc, mediated by Fabpl4xat-132-driven Cre-recombinase, suppresses Apc-dependent intestinal tumorigenesis in adult ApcMin/+ mice, without apparent effect on normal intestinal mucosa...
  21. ncbi Risk and risk reduction involving arginine intake and meat consumption in colorectal tumorigenesis and survival
    Jason A Zell
    Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA 92697 7550, USA
    Int J Cancer 120:459-68. 2007
    ..Our results suggest important roles for arginine and meat consumption in CRC pathogenesis, and have implications for CRC prevention...
  22. ncbi Mitochondrial perturbation attenuates bile acid-induced cytotoxicity
    C M Payne
    Department of Cell Biology and Anatomy, University of Arizona, Tucson, 85724, USA
    Cell Biol Toxicol 21:215-31. 2005
    ..These findings strongly implicate mitochondrial crosstalk with apoptotic signaling pathways and mitochondrial-nucleolar crosstalk in the development of apoptosis resistance in the colon...
  23. pmc Induction of spermidine/spermine N1-acetyltransferase (SSAT) by aspirin in Caco-2 colon cancer cells
    Naveen Babbar
    The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
    Biochem J 394:317-24. 2006
    ..These results suggest that activation of SSAT by aspirin and different NSAIDs may be a common property of NSAIDs that plays an important role in their chemopreventive actions in colorectal cancer...
  24. ncbi Crypt-restricted loss and decreased protein expression of cytochrome C oxidase subunit I as potential hypothesis-driven biomarkers of colon cancer risk
    Claire M Payne
    Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, 85724
    Cancer Epidemiol Biomarkers Prev 14:2066-75. 2005
    ..The results suggest, however, that aberrant cytochrome c oxidase subunit I expression may be a better biomarker than loss of apoptosis competence for increased colon cancer risk...
  25. ncbi Bile acid induces hydrophobicity-dependent membrane alterations
    Sandeep Akare
    Arizona Cancer Center, Department of Cell Biology and Anatomy, University of Arizona, 1515 N Campbell Avenue, Tucson, Arizona 85724, United States
    Biochim Biophys Acta 1735:59-67. 2005
    ....
  26. ncbi Ursodeoxycholic acid can suppress deoxycholic acid-induced apoptosis by stimulating Akt/PKB-dependent survival signaling
    Eunok Im
    Arizona Cancer Center, Department of Cell Biology and Anatomy, University of Arizona, Tucson, Arizona 85724, USA
    Nutr Cancer 51:110-6. 2005
    ..These results suggest that UDCA can protect HCT116 cells against DCA-induced apoptosis by stimulating Akt-dependent survival signaling...
  27. ncbi Assessment of apoptosis by immunohistochemical markers compared to cellular morphology in ex vivo-stressed colonic mucosa
    Hana Holubec
    Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA
    J Histochem Cytochem 53:229-35. 2005
    ..The antibody to c-PARP, though specific for apoptotic cells, had low usefulness, and the antibody to AIF was relatively nonspecific, under our conditions...
  28. ncbi Apoptosis resistance in Barrett's esophagus: ex vivo bioassay of live stressed tissues
    Katerina Dvorakova
    Department of Biology and Anatomy, College of Medicine, The University of Arizona, Tucson, Arizona
    Am J Gastroenterol 100:424-31. 2005
    ..The major goal of this study is to compare sensitivity to apoptosis induced by the bile acid, deoxycholate (DOC), a known inducer of apoptosis, in normal esophageal squamous epithelium, normal colon epithelium, and BE...
  29. ncbi Bile acids as carcinogens in human gastrointestinal cancers
    H Bernstein
    Department of Microbiology and Immunology, College of Medicine, University of Arizona, Tucson AZ 85724, USA
    Mutat Res 589:47-65. 2005
    ....
  30. ncbi The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis
    Hagit F Yerushalmi
    Gastrointestinal Cancer Program, Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA
    Mol Carcinog 45:93-105. 2006
    ..In the colon, Nos2 is required for the arginine-induced increase in tumor number and incidence...
  31. ncbi Identification of S-nitrosylated proteins after chronic exposure of colon epithelial cells to deoxycholate
    Monique Dall'Agnol
    Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ, USA
    Proteomics 6:1654-62. 2006
    ..These results broaden our knowledge of potential signal transduction pathways that may lead to the development of new biomarkers and therapy targets...
  32. ncbi Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence
    Sandeep Akare
    Department of Cell Biology and Anatomy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
    Int J Cancer 119:2958-69. 2006
    ..In summary, our data shows that UDCA modulates chromatin by inducing histone hypoacetylation and induces differentiation and senescence in colon cancer cells...
  33. ncbi Esophageal acid exposure at pH < or = 2 is more common in Barrett's esophagus patients and is associated with oxidative stress
    K Dvorak
    Department of Cell Biology and Anatomy, The University of Arizona, Tucson, AZ 85724, USA
    Dis Esophagus 19:366-72. 2006
    ..In vitro studies using brief pH 2 exposure are biologically relevant to the clinical situation. Our studies indicate that such exposure induces oxidative stress. This stress may cause DNA damage, mutations and progression to cancer...
  34. pmc Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity
    Ashley A Powell
    Cancer Biology Interdisciplinary Program, University of Arizona, Arizona Cancer Center, Tucson, AZ 85724, USA
    BMC Cancer 6:219. 2006
    ..The present study was carried out to determine whether there is overlap in signaling pathways activated by tumorogenic bile acid DCA and chemopreventive bile acid UDCA...
  35. ncbi Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells
    C M Payne
    Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ 85724 5044, USA
    Carcinogenesis 28:215-22. 2007
    ..The NF-kappaB-activating pathways, induced by the dietary-related endogenous detergent DOC, provide mechanisms for promotion of colon cancer and identify possible new targets for chemoprevention...
  36. ncbi Reduced Pms2 expression in non-neoplastic flat mucosa from patients with colon cancer correlates with reduced apoptosis competence
    Harris Bernstein
    Department of Cell Biology, College of Medicine, University of Arizona, Tucson, AZ, USA
    Appl Immunohistochem Mol Morphol 14:166-72. 2006
    ..Immunohistochemical determination of reduced Pms2 expression, upon further testing, may prove to be a promising early biomarker of risk of progression to malignancy...
  37. ncbi Role of polyamines in arginine-dependent colon carcinogenesis in Apc(Min) (/+) mice
    Hagit F Yerushalmi
    Gastrointestinal Cancer Program, Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA
    Mol Carcinog 45:764-73. 2006
    ..Inhibition of polyamine synthesis suppresses the arginine-dependent risk of colon tumorigenesis, resulting in apoptosis induction and decreased tumorigenesis, in this murine model...
  38. ncbi Unique dietary-related mouse model of colitis
    Harris Bernstein
    Department of Cell Biology and Anatomy, College of Medicine, Tucson, AZ 85724, USA
    Inflamm Bowel Dis 12:278-93. 2006
    ..Deoxycholate (DOC) is increased in the colonic contents in response to a high-fat diet. Thus, an elevated level of DOC in the colonic lumen may play a role in the natural course of development of IBD...
  39. ncbi Deoxycholic acid induces intracellular signaling through membrane perturbations
    Samira Jean-Louis
    Cancer Biology Interdisciplinary Program, Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
    J Biol Chem 281:14948-60. 2006
    ..Collectively, these data suggest that bile acid-induced signaling is initiated through alterations of the plasma membrane structure and the redistribution of cholesterol...
  40. ncbi Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells
    Anne Christine Goulet
    Department of Pathology, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
    Carcinogenesis 26:109-17. 2005
    ..These new data provide valuable insights into the biological effects of SeMet at clinically relevant concentrations...