Dietary Putrescine Reduces the Intestinal Anticarcinogenic Activity of Sulindac in a Murine Model of Familial Adenomatous Polyposis

Ignatenko, Natalia A.; Besselsen, David G.; Roy, Upal Kunal Basu; Stringer, David E.; Blohm-Mangone, Karen; Padilla-Torres, Jose L.; Guillen-R, Jose M.; Gerner, Eugene W.

doi:10.1207/s15327914nc5602_8

Cited by 35 publications

(31 citation statements)

References 38 publications

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“…The tumor suppression effect of the non-steroidal anti-inflammatory drug sulindac is reduced by dietary polyamines (54). Understanding polyamine transport mechanisms may be important for the development of new strategies for cancer treatment and chemoprevention.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Diamine Exporter in Colon Epithelial Cells

Uemura

Yerushalmi

Tsaprailis³

et al. 2008

Journal of Biological Chemistry

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SLC3A2, a member of the solute carrier family, was identified by proteomics methods as a component of a transporter capable of exporting the diamine putrescine in the Chinese hamster ovary (CHO) cells selected for resistance to growth inhibition by high exogenous concentrations of putrescine. Putrescine transport was increased in inverted plasma membrane vesicles prepared from cells resistant to growth inhibition by putrescine compared with transport in inverted vesicles prepared from non-selected cells. Knockdown of SLC3A2 in human cells, using short hairpin RNA, caused an increase in putrescine uptake and a decrease in arginine uptake activity. SLC3A2 knockdown cells accumulated higher polyamine levels and grew faster than control cells. The growth of SLC3A2 knockdown cells was inhibited by high concentrations of putrescine. Knockdown of SLC3A2 reduced export of polyamines from cells. Expression of SLC3A2 was suppressed in human HCT116 colon cancer cells, which have an activated K-RAS, compared with their isogenic clone, Hkh2 cells, which lack an activated K-RAS allele. Spermidine/ spermine N 1 -acetyltransferase (SAT1) was co-immunoprecipitated by an anti-SLC3A2 antibody as was SLC3A2 with an anti-SAT1 antibody. SLC3A2 and SAT1 colocalized on the plasma membrane. These data provide the first molecular characterization of a polyamine exporter in animal cells and indicate that the diamine putrescine is exported by an arginine transporter containing SLC3A2, whose expression is negatively regulated by K-RAS. The interaction between SLC3A2 and SAT1 suggests that these proteins may facilitate excretion of acetylated polyamines.Polyamines are essential for normal cellular functions (1, 2). They bind to intracellular polyanions such as nucleic acids and ATP and modulate their functions (3). Intracellular polyamine content is increased in response to growth stimuli (4) and regulated by biosynthesis and degradation (5). Uptake and export also play important roles in the regulation of cellular polyamine levels (5).In recent years, polyamine transporters have been identified in bacteria, yeast, and protozoa, and their properties have been studied. In Escherichia coli, polyamine uptake is mediated by three systems, the spermidine-preferential uptake system PotABCD (6, 7), the putrescine-specific uptake system Pot-FGHI (8), and PuuP (9). Export of polyamines is mediated by PotE (10), CadB (11), and MdtJI (12) in E. coli. Blt is a polyamine exporter in Bacillus subtilis (13). In Saccharomyces cerevisiae, uptake of polyamines is mediated by DUR3, SAM3, GAP1 (14, 15), and AGP2 (16) on the plasma membrane and UGA4 on vacuolar membranes (17). The four transporters TPO1-4 on the plasma membrane (18 -20) and TPO5 on the post-Golgi secretory vesicles (21) are polyamine exporters in yeast. A plasma membrane polyamine transporter, LmPot1, in protozoan parasite Leishmania major (22) has been described. In these unicellular organisms, polyamine transport involves protein channels.In animal cells, polyamine uptake is mediated, at least...

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Diamine Exporter in Colon Epithelial Cells

Uemura

Yerushalmi

Tsaprailis³

et al. 2008

Journal of Biological Chemistry

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“…To determine the relevance of this mechanism in animals, we treated Apc Min/+ mice, a model of human FAP, with sulindac alone or in combination with dietary putrescine (1% in the drinking water). Sulindac increased steady-state RNA levels and enzymatic activity of the polyamine catabolic enzyme SSAT (spermidine/spermine N 1 -acetyltransferase), and intestinal levels of monoacetylspermidine, spermidine and spermine, in the small intestine of mice [18]. Dietary putrescine increased intestinal putrescine contents while the combination of dietary putrescine and sulindac yielded the highest levels of intestinal putrescine.…”

Section: Influence Of Dietary Polyamines On Responses To Colon Cancermentioning

confidence: 97%

“…Dietary polyamines have been found to enhance intestinal and colonic tumorigenesis [17]. Recent studies from our group indicate that the primary effect of dietary putrescine is to increase tumour grade [18]. Our mouse studies used dietary putrescine levels (1% in the drinking water) that are equivalent to humans drinking 1-2 cups per day of grapefruit juice [19].…”

Section: Dietary Polyamines and Colon Carcinogenesismentioning

confidence: 99%

Impact of dietary amino acids and polyamines on intestinal carcinogenesis and chemoprevention in mouse models

Gerner

2007

Biochemical Society Transactions

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Colon cancer in humans is influenced by both genetic and dietary risk factors. The majority of colon cancers have somatic mutations in the APC (adenomatous polyposis coli) tumour-suppressor gene. Dietary arginine enhances the risk of APC-dependent colon carcinogenesis in mouse models by a mechanism involving NOS2 (nitric oxide synthase 2), as elimination of NOS2 alleles suppresses this phenotype. DFMO (difluoromethylornithine), a specific inhibitor of polyamine synthesis, also inhibits dietary arginine-induced colon carcinogenesis in C57BL/6J-Apc(Min)/J mice. The primary consequence of dietary arginine is to increase the adenoma grade in these mice. Either loss of NOS2 alleles or inhibition of polyamine synthesis suppresses the arginine-induced increase in adenoma grade. In addition to promoting intestinal carcinogenesis, polyamines can also reduce the efficacy of certain intestinal cancer chemopreventive agents. The NSAID (non-steroidal anti-inflammatory drug) sulindac is a potent inhibitor of intestinal carcinogenesis in the C57BL/6J-Apc(Min)/J mouse model and is used to treat humans with FAP (familial adenomatous polyposis). Dietary putrescine reduces the ability of sulindac to suppress intestinal tumorigenesis in the mouse model. These data suggest that reducing polyamine metabolism and dietary polyamine levels may enhance strategies for colon cancer chemoprevention.

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“…In fact, it is recommended that the dietary intake of putrescine be reduced in patients with familial adenomatous polyposis; in a murine model dietary putrescine increased the malignancy grade of adenomas [82]. Elevated concentrations of putrescine have also been detected in gastric carcinomas caused by…”

Section: Putrescine and Polyaminesmentioning

confidence: 99%

Toxicological Effects of Dietary Biogenic Amines

Ladero¹,

Calles-Enríquez²,

Fernández³

et al. 2010

CNF

444

294

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Biogenic amines (BAs) are defined as low molecular weight organic bases with biological activity. They are formed and degraded as part of the normal metabolism of microorganisms, plants and animals, in which they have important physiological functions. In humans, BAs are involved in brain activity, the regulation of body temperature and stomach pH, gastric acid secretion, the immune response, and cell growth and differentiation etc. However, the consumption of foods with high concentrations of BAs can induce adverse reactions such as nausea, headaches, rashes and changes in blood pressure. The accumulation of BAs in the food matrix is mainly due to the presence of bacteria able to decarboxylate certain amino acids. The most common and powerful BAs found in food are histamine, tyramine and putrescine. Their contents vary, sometimes reaching over 2 g per kg. Histamine is the only BA for which

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Dietary Putrescine Reduces the Intestinal Anticarcinogenic Activity of Sulindac in a Murine Model of Familial Adenomatous Polyposis

Cited by 35 publications

References 38 publications

Identification and Characterization of a Diamine Exporter in Colon Epithelial Cells

Identification and Characterization of a Diamine Exporter in Colon Epithelial Cells

Impact of dietary amino acids and polyamines on intestinal carcinogenesis and chemoprevention in mouse models

Toxicological Effects of Dietary Biogenic Amines

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