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2014 ; 355
(2
): 273-80
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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
PMID25304374
show 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 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 30?µM. 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
with the CD18 pancreatic carcinoma cells with AKR1B10 knockdown (tumor weight:
0.25?±?0.06?g vs. 0.52?±?0.07?g, p?=?0.01), and with OA treatment (tumor weight:
0.35?±?0.05?g vs. 0.52?±?0.07?g, p?=?0.05). Our findings indicate AKR1B10 is a
unique enzyme involved in pancreatic carcinogenesis via modulation of the
Kras-E-cadherin pathway.