An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma.

Abstract

Fumarate hydratase (FH) mutation causes hereditary type 2 papillary renal cell carcinoma (PRCC2). The main effect of FH mutation is fumarate accumulation. The current paradigm posits that the main consequence of fumarate accumulation is HIF-α stabilization. Paradoxically, FH mutation differs from other HIF-α stabilizing mutations, such as VHL and SDH mutations, in its associated tumor types. We identified that fumarate can directly up-regulate antioxidant response element (ARE)-controlled genes. We demonstrated that aldo-keto reductase family 1 member B10 (AKR1B10) is an ARE-controlled gene and is up-regulated upon FH knockdown as well as in FH null cell lines. AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2. This phenotype better explains the similarities between hereditary and sporadic PRCC2.

• Authors: Aikseng Ooi, Jing-Chii Wong, David Petillo, Douglas Roossien, Victoria Perrier-Trudova, Douglas Whitten, Bernice Wong Hui Min, Min-Han Tan, Zhongfa Zhang, Ximing J Yang, Ming Zhou, Betty Gardie, Vincent Molinié, Stéphane Richard, Puay Hoon Tan, Bin Tean Teh, Kyle A Furge
• Journal: Cancer cell (Cancer Cell) Vol. 20 Issue 4 Pg. 511-23 (Oct 18 2011) ISSN: 1878-3686 [Electronic] United States
• PMID: 22014576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intracellular Signaling Peptides and Proteins
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• NRF1 protein, human
• Nuclear Respiratory Factor 1
• RNA, Messenger
• AKR1B10 protein, human
• Aldo-Keto Reductases
• Aldehyde Reductase
• Fumarate Hydratase

Topics

• Aldehyde Reductase (genetics, metabolism)
• Aldo-Keto Reductases
• Antioxidants (metabolism)
• Carcinoma, Renal Cell (genetics, metabolism)
• Cell Line, Tumor
• Fumarate Hydratase (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics)
• Kelch-Like ECH-Associated Protein 1
• Kidney Neoplasms (genetics, metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Nuclear Respiratory Factor 1 (metabolism)
• Phenotype
• RNA, Messenger (metabolism)
• Response Elements (genetics, physiology)