Mutations in Fumarate Hydratase (FH) cause HLRCC, a kidney cancer syndrome related to BHD. FH is an enzyme involved in the TCA cycle and its deficiency results in the accumulation of fumarate within the cell. This accumulation leads to increased levels of HIF, via the inhibition of prolyl hydroxylases (PHDs), the enzymes that mark HIFα subunits for degradation. It is believed that increased HIF promotes tumourigenesis in FH-deficient cells.
FH-deficient cells are known to exhibit the Warburg effect, a phenomenon in which cancer cells shift to a high rate of glycolysis rather than oxidative phosphorylation. Tong et al. (2011) have recently investigated the metabolic state of the HLRCC cell line UOK262 and the effect of this glycolytic shift. They found that IRPs, proteins which are activated by cytosolic iron depletion, had increased activity in UOK262 cells, suggesting low levels of iron. PHDs require iron for their activity and therefore the low level of iron in FH-deficient cells could be an additional mechanism leading to increased levels of HIF.
The authors found that levels of the iron transporter DMT1 were extremely low in UOK262 cells, thereby explaining the reduced iron level and activation of IRPs. It was found that AMPK levels were reduced, which is caused by the glycolytic shift, and that this leads to the reduced DMT1 levels, revealing a role of AMPK in the regulation of intracellular iron metabolism. AMPK is known to stabilise p53, and so the authors then investigated whether p53 had an effect on DMT1. It was found that reduced p53 decreased DMT1 levels, suggesting AMPK regulates DMT1 expression through its effect on p53.
Then the authors compared the levels of AMPK, DMT1 and HIF-1α protein in UOK262 cells against the levels in a VHL-deficient cell line. In contrast to the UOK262 cells, VHL-deficient cells had higher levels of AMPK and DMT1 and lower levels of HIF-1α. This suggests that disease-specific therapies could be developed. Preston et al. (2010) showed that FLCN-null cells have increased levels of AMPK, suggesting BHD cells exhibit a metabolic profile more akin to VHL cells than HLRCC cells.
This new study correlates with the recent paper by Frezza et al. (2011) (discussed in a previous blog post) who found that haem metabolism was altered in FH-deficient cells and that the levels of three genes involved in haem degradation were increased. Haem degradation releases the bound iron, and therefore may be a mechanism used to increase the intracellular iron when levels are low.
More research is required to fully understand the metabolic profile of FH-deficient cells and how this can be exploited to develop effective therapies for HLRCC. Additionally, understanding how the metabolic profile of HLRCC cells differs from that of other inherited kidney cancer syndromes will help unravel the biology behind this class of diseases and perhaps lead to disease-specific therapies.
- Tong WH, Sourbier C, Kovtunovych G, Jeong SY, Vira M, Ghosh M, Romero VV, Sougrat R, Vaulont S, Viollet B, Kim YS, Lee S, Trepel J, Srinivasan R, Bratslavsky G, Yang Y, Linehan WM, & Rouault TA (2011). The Glycolytic Shift in Fumarate-Hydratase-Deficient Kidney Cancer Lowers AMPK Levels, Increases Anabolic Propensities and Lowers Cellular Iron Levels. Cancer cell, 20 (3), 315-27 PMID: 21907923
- Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A, Kalna G, Tomlinson IP, Pollard PJ, Watson DG, Deberardinis RJ, Shlomi T, Ruppin E, & Gottlieb E (2011). Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature, 477 (7363), 225-8 PMID: 21849978
- Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, & Tee AR (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30 (10), 1159-73 PMID: 21057536