Inhibition of aldose reductase prevents colon cancer metastasis

Ravinder Tammali, Aramati B M Reddy, Ashish Saxena, Piotr G. Rychahou, B. Mark Evers, Suimin Qiu, Sanjay Awasthi, Kota Ramana, Satish Srivastava

Research output: Contribution to journalArticle

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Abstract

Colon cancer is the third most common cause of cancer and is the second leading cause of cancer deaths in the USA. Although inhibition of aldose reductase (AR) is known to prevent human colon cancer cell growth in nude mice xenografts, the role of AR in the regulation of cancer metastasis is not known. We now demonstrate the mechanisms by which AR regulates colon cancer metastasis in vitro and in vivo. Inhibition of AR prevented the epidermal growth factor (EGF) or fibroblast growth factor (FGF)-induced migration and invasion of human colon cancer (HT29; KM20) cells by >70% and also inhibited (>80%) the adhesion of the cancer cells to endothelial cells. Treatment of endothelial cells with AR inhibitors significantly (∼85%) downregulated the EGF or FGF-induced expression of Inter-Cellular Adhesion Molecule-1, Vascular cell adhesion molecule-1 and vascular endothelial-cadherin. Furthermore, liver metastasis of green fluorescent protein-labeled KM20 cells injected into the spleen of athymic nude mice was significantly (>65%) prevented by AR inhibitor, fidarestat or ARsiRNA delivered systemically into the mice. Similar results were observed with HT29 cells. AR inhibition or ablation also prevented (70-90%) the increase in the levels of matrix metalloproteinase-2, cyclin D1, CD31, CD34 and the activation of nuclear factor-kappa-binding protein in metastatic liver. Thus, our results indicate that AR regulates cancer cell adhesion, invasion and migration events which initiate metastasis and therefore, AR inhibition could be a novel therapeutic approach for the prevention of colon cancer metastasis.

Original languageEnglish (US)
Pages (from-to)1259-1267
Number of pages9
JournalCarcinogenesis
Volume32
Issue number8
DOIs
StatePublished - 2011

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Aldehyde Reductase
Colonic Neoplasms
Neoplasm Metastasis
Nude Mice
HT29 Cells
Fibroblast Growth Factors
Epidermal Growth Factor
Cell Adhesion
Neoplasms
Endothelial Cells
Second Primary Neoplasms
Vascular Cell Adhesion Molecule-1
Liver
Matrix Metalloproteinase 2
Cyclin D1
Green Fluorescent Proteins
Heterografts
Cell Movement
Cause of Death
Carrier Proteins

ASJC Scopus subject areas

  • Cancer Research

Cite this

Tammali, R., Reddy, A. B. M., Saxena, A., Rychahou, P. G., Evers, B. M., Qiu, S., ... Srivastava, S. (2011). Inhibition of aldose reductase prevents colon cancer metastasis. Carcinogenesis, 32(8), 1259-1267. https://doi.org/10.1093/carcin/bgr102

Inhibition of aldose reductase prevents colon cancer metastasis. / Tammali, Ravinder; Reddy, Aramati B M; Saxena, Ashish; Rychahou, Piotr G.; Evers, B. Mark; Qiu, Suimin; Awasthi, Sanjay; Ramana, Kota; Srivastava, Satish.

In: Carcinogenesis, Vol. 32, No. 8, 2011, p. 1259-1267.

Research output: Contribution to journalArticle

Tammali, R, Reddy, ABM, Saxena, A, Rychahou, PG, Evers, BM, Qiu, S, Awasthi, S, Ramana, K & Srivastava, S 2011, 'Inhibition of aldose reductase prevents colon cancer metastasis', Carcinogenesis, vol. 32, no. 8, pp. 1259-1267. https://doi.org/10.1093/carcin/bgr102
Tammali R, Reddy ABM, Saxena A, Rychahou PG, Evers BM, Qiu S et al. Inhibition of aldose reductase prevents colon cancer metastasis. Carcinogenesis. 2011;32(8):1259-1267. https://doi.org/10.1093/carcin/bgr102
Tammali, Ravinder ; Reddy, Aramati B M ; Saxena, Ashish ; Rychahou, Piotr G. ; Evers, B. Mark ; Qiu, Suimin ; Awasthi, Sanjay ; Ramana, Kota ; Srivastava, Satish. / Inhibition of aldose reductase prevents colon cancer metastasis. In: Carcinogenesis. 2011 ; Vol. 32, No. 8. pp. 1259-1267.
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