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Deprecated: Implicit conversion from float 249.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cancer+Lett 2014 ; 355 (2): 273-80 Nephropedia Template TP
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Knockdown or inhibition of Aldo-keto reductase 1B10 inhibits pancreatic carcinoma growth via modulating Kras - E-cadherin pathway #MMPMID25304374
Zhang W; Li H; Yang Y; Liao J; Yang GY
Cancer Lett 2014[Dec]; 355 (2): 273-80 PMID25304374show ga
Aldo-keto reductase 1B10 (AKR1B10) has relatively specific lipid substrates including carbonyls, retinal and farnesal/geranylgeranial. Metabolizing these lipid substrates appears crucial to carcinogenesis, particularly for farnesal/geranylgeranial that involves in protein prenylation. Mutant Kras is a most common active oncogene in pancreatic cancer, and its activation requires protein prenylation. To directly determine the role of AKR1B10 in pancreatic carcinogenesis, we knocked down AKR1B10 in CD18 human pancreatic carcinoma cells using shRNA approach. Silencing AKR1B10 resulted in a significant inhibition of anchor-dependent growth (knockdown cells vs vector-control cells: 67 ± 9.5 colonies/HPF vs 170 ± 3.7 colonies/HPF, P < 0.01), invasion index (0.27 vs. 1.00, p<0.05), and cell migration (at 16 hours 9.2 ± 1.2% vs 14.0 ± 1.8%, at 24 hours 21.0 ± 1.1% vs 30.5 ± 3.5%, and at 48 hours 51.9 ± 5.7% vs 88.9 ± 3.0%, P < 0.01). Inhibition of AKR1B10 by oleanolic acid (OA) showed a dose-dependent inhibition of cell growth with IC50 at 30µM. Kras pull-down and Western blot analysis revealed a significant down-regulation of active form Kras and phosphorylated C-Raf, and Erk, as well as an up-regulation of E-cadherin. A significant reduction of in vivo tumor growth was observed in nude mice implanted the CD18 pancreatic carcinoma cells with AKR1B10 knockdown (tumor weight: 0.25 ± 0.06g vs. 0.52 ± 0.07g, P = 0.01), and with OA treatment (tumor weight: 0.35 ± 0.05g vs. 0.52 ± 0.07g, P = 0.05). Our findings indicate AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis via modulation of Kras-E-Cadherin pathway.