LINKS TO HLRCC RESEARCH - Cell Chemistry and Cell Lines


The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-κB signaling. Shanmugasundaram K, Nayak B, Shim EH, Livi CB, Block K, Sudarshan S, 2014

Identifies Tank binding kinase 1 - TBK1 as a novel putative therapeutic target for the treatment of aggressive fumarate-driven tumors

Genetic variants in genes of tricarboxylic acid cycle key enzymes are associated with prognosis of patients with non-small cell lung cancer. Guo X, Li D, Wu Y, Chen Y, Zhou X, Wang X, Huang X, Li X, Yang H, and Xing J, 2014

This article reports that a particular FH alteration was the primary risk factor contributing to Overall Survival of NSCLC patients.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a rapid autopsy report of metastatic renal cell carcinoma Aaron M. Udager, Ajjai Alva, Ying-Bei Chen, Javed Siddiqui, Amir Lagstein, Satish K. Tickoo, Victor E. Reuter, Arul M. Chinnaiyian, and Rohit Mehra, 2014

This has a comprehensive description of the various cell types of the primary and metastatic sites.

High throughput synthetic lethality screen reveals a tumorigenic role of adenylate cyclase in fumarate hydratase-deficient cancer cells Michael Boettcher, Andrew Lawson, Viola Ladenburger, Johannes Fredebohm, Jonas Wolf, Jörg D Hoheisel, Christian Frezza and Tomer Shlomi, 2014

A paper showing that that further pathway targets exist specifically for HLRCC tumors.

Q&A: Targeting metabolism to diagnose and treat cancer Ralph J DeBerardinis, 2014 Alternative link

Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism Ming Yang, Huizhong Su, Tomoyoshi Soga, Kamil R Kranc, and Patrick J Pollard, 2014

Abstract starts: The hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl residues in its α subunit in an oxygen-dependent manner. The synergy between HLRCC and VHL is shown in the article.

A whole-cell electrochemical biosensing system based on bacterial inward electron flow for fumarate quantification Rong-Wei Sia, Dan-Dan Zhaia, Zhi-Hong Liaoa, Lu Gaoa, and Yang-Chun Yonga, 2014

Measurement of a high fumarate level can be useful in HLRCC diagnosis when no FH gene mutation has been found. This is a link to the abstract, the full article is available on subscription.

DisABLing Kidney Cancers Caused by Fumarate Hydratase Mutations. Kaelin WG Jr., 2014

Another article identifying specific targets for treatment of HLRCC kidney cancers. This is a link to the abstract, the full article is available on subscription.


Reversed argininosuccinate lyase activity in fumarate hydratase-deficient cancer cells Liang Zheng, Elaine D MacKenzie, Saadia A Karim, Ann Hedley, Karen Blyth, Gabriela Kalna, David G Watson, Peter Szlosarek, Christian Frezza and Eyal Gottlieb, 2013


A novel fumarate hydratase-deficient HLRCC kidney cancer cell line, UOK268: a model of the Warburg effect in cancer. Youfeng Yang, Vladimir Valera, Carol Sourbier, Cathy D. Vocke, Minghui Wei, Lisa Pike, Ying Huang, Maria A. Merino, Gennady Bratslavsky, Min Wu, Christopher J. Ricketts, W. Marston Linehan, 2012

This technology from the NIH describes the UOK 268 cell line, spontaneously immortalized renal tumor cell line from a primary tumor that may be of great interest to industry for studying HLRCC, following on the UOK 262 cell line and research on the earlier A549 FH deficient cells.

Pseudohypoxia, Mitochondrial Mutations, the Warburg Effect, and Cancer Edward Sanders, Biomedical Research 2012

This has a comprehensive description taken from the latest research papers of the current research into HLRCC cell chemistry.

Decoding key nodes in the metabolism of cancer cells:sugar & spice and all things nice Reuben J. Shaw and Lewis C. Cantley, 2012

This article describes the Krebs Cycle and chemistry , not specifically related to HLRCC.

Fumarate hydratase inactivation in renal tumors: HIF-1α, NRF2, and "cryptic targets" of transcription factors Aikseng Ooi and Kyle A. Furge, 2012

This article is in Chinese Jounal of Cancer and describes a lot of current theories.


Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status Chiara Bardella, Mona El-Bahrawy, Norma Frizzell, Julie Adam, Nicola Ternette, Emine Hatipoglu Kimberley Howarth Linda O'Flaherty Ian Roberts, Gareth Turner, Jennifer Taylor, Konstantinos Giaslakiotis, Valentine M Macaulay, Adrian L Harris, Ashish Chandra, Heli J Lehtonen, Virpi Launonen, Lauri A Aaltonen, Christopher W Pugh, Radu Mihai, David Trudgian, Benedikt Kessler, John W Baynes, Peter J Ratcliffe1, Ian P Tomlinson, and Patrick J Pollard, 2011

Researchers in Oxford, UK have found that a chemical compound called 2SC which is S-(2-succinyl) cysteine (termed protein succination) is found only in HLRCC tumors and not in other tumors and is now being routinely used as a low cost, quick screening aid. This thesis An Investigation of Mitochondrial Bioenergetics and the Turnover of Succinated Proteins in the Adipocyte during Diabetes Tanis R, 2014 links research with Diabetes Type II. This article Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Chen YB, Brannon AR, Toubaji A, Dudas ME, Won HH, Al-Ahmadie HA, Fine SW, Gopalan A, Frizzell N, Voss MH, Russo P, Berger MF, Tickoo SK, Reuter VE.,2014 confirms the testing for 2SC to distinguish HLRCC tumors from others. It also has a detailed description of HLRCC kidney cancers.

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase Christian Frezza, Liang Zheng,Ori Folger, Kartik N. Rajagopalan, Elaine D. MacKenzie, Livnat Jerby, Massimo Micaroni, Barbara Chaneton, Julie Adam, Ann Hedley, Gabriela Kalna, Ian P. M. Tomlinson, Patrick J. Pollard, Dave G. Watson, Ralph J. Deberardinis, Tomer Shlomi,Eytan Ruppin, Eyal Gottlieb, 2011

This is exciting new research describing a cell pathway which when blocked in a HLRCC cancer cell will cause that cell to die, but allow normal cells to live.

Predicting selective drug targets in cancer through metabolic networks Ori Folger, Livnat Jerby, Christian Frezza, Eyal Gottlieb, Eytan Ruppin, and Tomer Shlomi, 2011

This article describes the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific down regulation of gene expression and somatic mutations are compiled. This includes HLRCC.

Succination of Keap1 and Activation of Nrf2-Dependent Antioxidant Pathways in FH-Deficient Papillary Renal Cell Carcinoma Type 2 Lisa Kinch, Nick V. Grishin, James Brugarolas, Cancer Cell, Volume 20, Issue 4, 418-420, 18 October 2011

An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma 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 Tehsend email, Kyle A. Furge, Cancer Cell, Volume 20, Issue 4, 511-523, 18 October 2011

Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling Julie Adam, Emine Hatipoglu, Linda O'Flaherty, Nicola Ternette, Natasha Sahgal, Helen Lockstone, Dilair Baban, Emma Nye, Gordon W. Stamp, Kathryn Wolhuter, Marcus Stevens, Roman Fischer, Peter Carmeliet, Patrick H. Maxwell, Chris W. Pugh, Norma Frizzell, Tomoyoshi Soga, Benedikt M. Kessler, Mona El-Bahrawy, Peter J. Ratcliffesend email, Patrick J. Pollard, Cancer Cell, Volume 20, Issue 4, 524-537, 18 October 2011


UOK 262: Fumarate Hydratase (-/-) Hereditary Leiomyomatosis Renal Cell Carcinoma: In Vitro and In Vivo Model of an Aberrant Energy Metabolic Pathway in Human Cancer Youfeng Yang, Vladimir A. Valera, Hesed M. Padilla-Nash, Carole Sourbier, Cathy D. Vocke, Manish A. Vira, Mones S. Abu-Asab, Gennady Bratslavsky, Maria Tsokos, Maria J. Merino, Peter A. Pinto, Ramaprasad Srinivasan, Thomas Ried, Len Neckers, and W. Marston Linehan1, 2010

This technology from the NIH describes the UOK 262 cell line, spontaneously immortalized renal tumor cell line from a metastatic tumor that may be of great interest to industry for studying HLRCC, following on the research on the earlier A549 FH deficient cells.

Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma Carole Sourbier, Vladimir Valera-Romero, Alessio Giubellino, Youfeng Yang, Sunil Sudarshan, Len Neckers, and W Marston Linehan, 2010

This article describes in vitro and in an in vivo xenograft model that increasing ROS level in HLRCC above a certain threshold can induce HLRCC-tumor cell death. Increasing tumor ROS with bortezomib in combination with cisplatin represents a novel targeted therapeutic approach to treat advanced HLRCC-associated renal tumors.


LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancerHan Xie, Vladimir A. Valera, Maria J. Merino, Angela M. Amato, Sabina Signoretti, William M. Linehan, Vikas P. Sukhatme and Pankaj Seth, 2009

Describes possible treatment of HLRCC by lactate dehydrogenase-A (LDH-A) blockade.

Fumarate Hydratase Deficiency in Renal Cancer Induces Glycolytic Addiction and Hypoxia-Inducible Transcription Factor 1α Stabilization by Glucose-Dependent Generation of Reactive Oxygen Species Sunil Sudarshan, Carole Sourbier, Hye-Sik Kong, Karen Block, Vladimir A, Valera Romero, Youfeng Yang, Cynthia Galindo, Mehdi Mollapour, Bradley Scroggins, Norman Goode, Min-Jung Lee, Campbell W. Gourlay, Jane Trepel, W. Marston Linehan, and Len Neckers, 2009

A highly technical discussion of cell chemistry.


Compensatory alterations in energy homeostasis characterized in uterine tumors from hereditary leiomyomatosis and renal cell cancer Catherino WH, Mayers CM, Mantzouris T, Armstrong AY, Linehan WM, Segars JH, 2007

This is a link to the abstract. The full article is available on subscription. It describes the enzyme differences between HLRCC fibroids and non-HLRCC fibroids compensating for the loss of FH.

Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway Patrick J. Pollard, Bradley Spencer-Dene, Deepa Shukla, Kimberley Howarth, Emma Nye, Mona El-Bahrawy, Maesha Deheragoda, Maria Joannou, Stuart McDonald, 2007

Technical article describing in vivo that pseudohypoxic drive, resulting from HIF1α (and HIF2α) overexpression, is a direct consequence of Fh1 inactivation. The mouse model advances the understanding of biochemical pathways linking mitochondrial dysfunction and tumorigenesis and will allow testing of potential therapies for renal neoplasms.

Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells Mariia Yuneva, Nicola Zamboni, Peter Oefner, Ravi Sachidanandam,and Yuri Lazebnik, 2007

This article describes the Krebs Cycle and chemistry relating to cell death, not specifically related to HLRCC.

Gives a news office view of the article.


Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer A King, M A Selak, and E Gottlieb, 2006

A highly technical discussion of cell chemistry - good schematic diagrams.

Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer M Pithukpakorn, M‐H Wei, O Toure, P J Steinbach, G M Glenn, B Zbar, W M Linehan, and J R Toro, 2006

The enzyme test seems to be unavailable now from most laboratories due to difficulties in interpreting results.

Fumarase and Oxidative Metabolism

Scroll down to technical description and diagram of the Citric Acid Cycle, also known as the Krebs Cycle.


HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability Jennifer S. Isaacs, Yun Jin Jung, David R. Mole,Sunmin Lee,Carlos Torres-Cabala,Yuen-Li Chung,Maria Merino,Jane Trepel,Berton Zbar,Jorge Toro,Peter J. Ratcliffe,W. Marston Linehan and Len Neckers, 2005

A highly technical discussion of cell chemistry.

Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations P.J. Pollard, J.J. Brière, N.A. Alam, J. Barwell, E. Barclay, N.C. Wortham, T. Hunt, M. Mitchell, S. Olpin, S.J. Moat, I.P. Hargreaves, S.J. Heales, Y.L. Chung, J.R. Griffiths, A. Dalgleish, J.A. McGrath, M.J. Gleeson, S.V. Hodgson, R. Poulsom, P. Rustin and I.P.M. Tomlinson, 2005

In the Discussion "Our results have demonstrated that bi-allelic FH mutations, whether in HLRCC tumours or in cells from fumarase deficiency patients, result in raised levels of both fumarate and succinate. Bi-allelic SDHB mutations predominantly cause raised levels of succinate. We have additionally shown that benign and malignant tumours in the HLRCC syndrome exhibit accumulation of the HIF1α protein, the central signalling molecule in the hypoxia pathway."

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Last modified: December 13 2017 22:29:31.