The publisher's final edited version of this article is available at Oncogene. 2018 Oct;37(40):5435-5450. doi: 10.1038/s41388-018-0315-z. Epub 2018 Jun 5. Non-commercial use onlyThis study was funded by Cancer Research UK, the German Research Foundation (FOR2314) and the German Cancer Aid (111917)

AA Hakimi

AJ Majmundar

AL Hughes

Almut Schulze

AR Mullen

Arvin M. Gouw

B Li

B Perroud

B Qiu

Barrie Peck

Beatrice Dankworth

Becky Saunders

C Bierl

C Gorrini

Cancer Genome Atlas Research N.

CM Metallo

CV Dang

Dean W. Felsher

DR Wise

EA Singer

EG Bligh

EH Shroff

F Gatto

GJ Warner

GL Semenza

HA Drabkin

Heike Miess

IS Harris

J Jones

JD Gordan

Julian Downward

K Bensaad

K Saito

L Gossage

L Jiang

L Li

LB Sullivan

M Faronato

M Gerlinger

Mathias Rosenfeldt

Michael Howell

Ming Jiang

ML Gumz

MP Murphy

MP Wymann

MV Yusenko

MY Kwon

N Avissar

N Malo

O Iliopoulos

O Radmark

PA Carroll

R Beroukhim

R Brigelius-Flohe

RA Cairns

RL Gebhard

S Dalleau

SJ Dixon

SW Tang

Werner Schmitz

WS Yang

X Tang

Y Xie

Oncogene

English

Miess, H

Dankworth, B

Gouw, AM

Rosenfeldt, M

Schmitz, W

Jiang, M

Saunders, B

Howell, M

Downward, J

Felsher, DW

Peck, B

Schulze, A

Queen Mary Research Online

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma

Crossref

Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the depletion of glutamine or cystine, two amino acids required for glutathione (GSH) synthesis. Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells. Inhibition of GSH synthesis triggered ferroptosis, an iron-dependent form of cell death associated with enhanced lipid peroxidation. VHL is a major tumour suppressor in ccRCC and loss of VHL leads to stabilisation of hypoxia inducible factors HIF-1α and HIF-2α. Restoration of functional VHL via exogenous expression of pVHL reverted ccRCC cells to an oxidative metabolism and rendered them insensitive to the induction of ferroptosis. VHL reconstituted cells also exhibited reduced lipid storage and higher expression of genes associated with oxidiative phosphorylation and fatty acid metabolism. Importantly, inhibition of β-oxidation or mitochondrial ATP-synthesis restored ferroptosis sensitivity in VHL reconstituted cells. We also found that inhibition of GSH synthesis blocked tumour growth in a MYC-dependent mouse model of renal cancer. Together, our data suggest that reduced fatty acid metabolism due to inhibition of β-oxidation renders renal cancer cells highly dependent on the GSH/GPX pathway to prevent lipid peroxidation and ferroptotic cell death

Miess, Heike

Dankworth, Beatrice

Gouw, Arvin M

Rosenfeldt, Mathias

Schmitz, Werner

Jiang, Ming

Saunders, Becky

Howell, Michael

Downward, Julian

Felsher, Dean W

Peck, Barrie

Schulze, Almut

UCL Discovery

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/62485/Peck.%202018.%20glutathione%20redox%20system.pdf?sequence=2&isAllowed=y

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma

Abstract

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Queen Mary Research Online

Crossref

UCL Discovery