We have recently demonstrated that aldose reductase (AR), an enzyme that catalyzes the reduction of reactive oxygen species-induced lipid peroxidation-derived lipid aldehydes and their glutathione (GSH)- conjugates (GS-LDAs), is an essential mediator of oxidative stress-induced carcinogenic signals. Our results from the previous project period have shown that inhibition of AR prevents the growth of human colon cancer cells by inhibiting the expression of NF-?B-dependent inflammatory markers. We have also shown that inhibition of AR prevents growth of human colon cancer cells in nude mouse xenografts, as well as azoxymethane-induced aberrant crypt foci formation in a mouse model. Further, we have also shown that inhibition of AR prevents colon cancer metastasis by preventing cancer cell invasion, migration and adhesion, as well as angiogenesis. Although we have shown that AR-catalyzed reduced products of GS-LDAs, such as GS-DHN, transduce carcinogenic signals downstream to protein kinase C (PKC), the molecular mechanisms that regulate cellular redox homeostasis leading to carcinogenesis are not clearly understood. We hypothesize that lipid aldehydes and GS-conjugates mediate anti-carcinogenic and pro-carcinogenic signaling cascades that lead to colon cancer growth and metastasis. Our goal in this project is to determine the mechanisms by which AR-catalytic activity plays a critical role in the regulation of colon carcinogenesis using human colon cancer cells, isolated human colon cancer stem cells in vitro, as well as in vivo orthotopic mouse models. Our long-term goal is to develop inhibitors of AR as safe and effective preventive measures for colorectal cancer growth and metastasis.
Our specific aims are to: 1) determine how glutathione-lipid aldehydes (GS-LDAs) regulate NF-kB and Nrf-2 pathways that mediate CRC cell growth/death;2) elucidate how AR inhibition prevents growth and metastasis of human CRC biopsy samples and colon cancer stem cells implanted in athymic nude mice;and 3) determine how AR inhibition prevents the survival of colon cancer stem cells. Completion of this project will elucidate the molecular mechanisms by which AR regulates cellular redox homeostasis, carcinogenesis and tumor growth and metastasis, and lay the foundation for the use of AR inhibitors as novel chemopreventive drugs for colorectal cancer.

Public Health Relevance

Colon cancer is the third leading cause of death from cancer in the US. Our project will determine the mechanisms through which aldose reductase inhibitors prevent the development and spread of colon cancers, and should ultimately lead to the development of new chemopreventive/chemotherapeutic approaches to prevent death from colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA129383-06A1
Application #
8503346
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2007-12-01
Project End
2018-03-31
Budget Start
2013-04-09
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$310,970
Indirect Cost
$109,695
Name
University of Texas Medical Br Galveston
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Shukla, Kirtikar; Sonowal, Himangshu; Saxena, Ashish et al. (2017) Aldose reductase inhibitor, fidarestat regulates mitochondrial biogenesis via Nrf2/HO-1/AMPK pathway in colon cancer cells. Cancer Lett 411:57-63
Awasthi, Yogesh C; Ramana, Kota V; Chaudhary, Pankaj et al. (2017) Regulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity. Free Radic Biol Med 111:235-243
Sonowal, Himangshu; Pal, Pabitra B; Wen, Jian-Jun et al. (2017) Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity. Sci Rep 7:3182
Saxena, Ashish; Tammali, Ravinder; Ramana, Kota V et al. (2017) Aldose reductase inhibitor, fidarestat prevents high-fat diet-induced intestinal polyps in ApcMin/+ mice. Curr Cancer Drug Targets :
Saxena, Ashish; Shoeb, Mohammad; Tammali, Ravinder et al. (2014) Aldose reductase inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Cancer Lett 355:141-7
Li, Yang; Zhao, Zhongxin; Xu, Chuanhui et al. (2014) HMGA2 induces transcription factor Slug expression to promote epithelial-to-mesenchymal transition and contributes to colon cancer progression. Cancer Lett 355:130-40
Shoeb, Mohammad; Ansari, Naseem H; Srivastava, Satish K et al. (2014) 4-Hydroxynonenal in the pathogenesis and progression of human diseases. Curr Med Chem 21:230-7
Shoeb, Mohammad; Ramana, Kota V; Srivastava, Satish K (2013) Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors. Free Radic Biol Med 63:280-90
Saxena, Ashish; Shoeb, Mohammad; Ramana, Kota V et al. (2013) Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell death 4 (PDCD4) expression. Eur J Cancer 49:3311-9
Saxena, Ashish; Tammali, Ravinder; Ramana, Kota V et al. (2013) Aldose Reductase Inhibition Prevents Colon Cancer Growth by Restoring Phosphatase and Tensin Homolog Through Modulation of miR-21 and FOXO3a. Antioxid Redox Signal 18:1249-62

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