Do HLRCC and BHD Syndrome share a similar obligation to respire anaerobically?

Yang et al, (2010) describe the generation and characterisation of an immortalised hereditary leiomyomatosis renal cell carcinoma (HLRCC) cell line, derived from a human patient. HLRCC is a form of inherited kidney cancer in which affected individuals are at risk of developing cutaneous and uterine leiomyomas and kidney cancer, characterized by germline mutation of the Krebs cycle enzyme fumarate hydratase (FH; Launonen et al, 2001). Incidences of renal cancer in HLRCC are highly aggressive and often result in metastasis.

The dependence of HLRCC tumours on glycolysis as a means of obligate anaerobic respiration, coupled with their impaired mitochondrial respiration, mark this renal cancer as a unique example of Warburg’s hypothesis. This hypothesis suggests the tumours forgo the Kreb’s cycle as a means of ATP generation, instead, preferentially using glyclolysis (Ganapathy et al, 2009).

These findings suggest that interference of glycolytic flux may represent a targeted approach to therapy for HLRCC. BHD syndrome is phenotypically similar to HLRCC in that it is characterised by the growth of cutaneous and renal lesions (as well as pulmonary cysts) albeit less severely. Both syndromes share an element of HIF dysfunction: biallelic loss of FH results in aberrant signalling mediated through HIF dependent pathways (Sudarshan et al, 2007) and Weppler et al, (2008) presented data at the Inaugural BHD Symposium which showed that BHD patients may have aberrant HIF activity that was thought to contribute to the development of skin and kidney tumours.

A method similar to that used by Yang et al, (2010) could be used on the FLCN null cell line UOK257 (human RCC derived from a BHD patient), or any BHD animal model, to investigate the status of glycolysis and aerobic respiration could prove useful in expanding our understanding of the pathogenic mechanism underlying BHD syndrome.


Ganapathy V,Thangaraju M, Prasad PD. 2009. Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond. Pharmacology & Therapeutics, 121(1); 29-40

Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, Sistonen P, Herva R, Aaltonen LA. 2001. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 98:3387–3392.

Sudarshan S, Linehan WM, Neckers L. 2007. HIF and fumarate hydratase in renal cancer.  Br J Cancer. 96(3): 403–407.

Weppler SA et al, 2008. Folliculin-dependent regulation of HIF2-alpha. Familial Cancer, 7 (Supplement 1)

Yang Y, Valera VA, Padilla-Nash HM, Sourbier C, Vocke CD, Vira MA, Abu-Asab MS, Bratslavsky G, Tsokos M, Merino MJ, Pinto PA, Srinivasan R, Ried T, Neckers L, Linehan WM. 2010. UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer. Cancer Genet Cytogenet. 196(1):45-55.

Yang Y, Nash HM, Vira MA, Abu-Asab MS, Val D, Worrell R, Tsokos M, Merino MJ, Pavlovich CP, Ried T, Linehan WM, and Vocke CD.2008. The UOK 257 Cell Line – A Novel Model for Studies of the Human Birt-Hogg-Dubé Gene Pathway. Cancer Genet Cytogenet. 180(2): 100–109.

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