Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels. Additionally, we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1alpha stabilization. Further, we have found that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1alpha stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010683-07
Application #
8349105
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2011
Total Cost
$344,370
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Sourbier, Carole; Scroggins, Bradley T; Mannes, Philip Z et al. (2015) Tonantzitlolone cytotoxicity toward renal cancer cells is PKC?- and HSF1-dependent. Oncotarget 6:29963-74
Khiati, Salim; Baechler, Simone A; Factor, Valentina M et al. (2015) Lack of mitochondrial topoisomerase I (TOP1mt) impairs liver regeneration. Proc Natl Acad Sci U S A 112:11282-7
Moses, Michael A; Neckers, Len (2015) The GLU that holds cancer together: targeting GLUtamine transporters in breast cancer. Cancer Cell 27:317-9
Sourbier, Carole; Ricketts, Christopher J; Matsumoto, Shingo et al. (2014) Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell 26:840-850
Khiati, Salim; Dalla Rosa, Ilaria; Sourbier, Carole et al. (2014) Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin Cancer Res 20:4873-81
Sourbier, Carole; Scroggins, Bradley T; Ratnayake, Ranjala et al. (2013) Englerin A stimulates PKC? to inhibit insulin signaling and to simultaneously activate HSF1: pharmacologically induced synthetic lethality. Cancer Cell 23:228-37
Neckers, Len; Ricketts, Christopher J; Marston Linehan, W (2013) New Insights into von Hippel-Lindau Function Highlighted by Investigation of the Trichloroethylene-Induced p.P81S Hotspot Mutation. J Natl Cancer Inst 105:1339-40
Douarre, Celine; Sourbier, Carole; Dalla Rosa, Ilaria et al. (2012) Mitochondrial topoisomerase I is critical for mitochondrial integrity and cellular energy metabolism. PLoS One 7:e41094
Sourbier, Carole; Valera-Romero, Vladimir; Giubellino, Alessio et al. (2010) Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma. Cell Cycle 9:4183-9
Linehan, W Marston; Bratslavsky, Gennady; Pinto, Peter A et al. (2010) Molecular diagnosis and therapy of kidney cancer. Annu Rev Med 61:329-43

Showing the most recent 10 out of 14 publications