TY  - JOUR
A1  - Peck, Barrie
A1  - Schug, Zachary T.
A1  - Zhang, Qifeng
A1  - Dankworth, Beatrice
A1  - Jones, Dylan T.
A1  - Smethurst, Elizabeth
A1  - Patel, Rachana
A1  - Mason, Susan
A1  - Jian, Ming
A1  - Saunders, Rebecca
A1  - Howell, Michael
A1  - Mitter, Richard
A1  - Spencer-Dene, Bradley
A1  - Stamp, Gordon
A1  - McGarry, Lynn
A1  - James, Daniel
A1  - Shanks, Emma
A1  - Aboagye, Eric O.
A1  - Critchlow, Susan E.
A1  - Leung, Hing Y.
A1  - Harris, Adrian L.
A1  - Wakelam, Michael J. O.
A1  - Gottlieb, Eyal
A1  - Schulze, Almut
T1  - Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments
JF  - Cancer & Metabolism
N2  - Background
Enhanced macromolecule biosynthesis is integral to growth and proliferation of cancer cells. Lipid biosynthesis has been predicted to be an essential process in cancer cells. However, it is unclear which enzymes within this pathway offer the best selectivity for cancer cells and could be suitable therapeutic targets.

Results
Using functional genomics, we identified stearoyl-CoA desaturase (SCD), an enzyme that controls synthesis of unsaturated fatty acids, as essential in breast and prostate cancer cells. SCD inhibition altered cellular lipid composition and impeded cell viability in the absence of exogenous lipids. SCD inhibition also altered cardiolipin composition, leading to the release of cytochrome C and induction of apoptosis. Furthermore, SCD was required for the generation of poly-unsaturated lipids in cancer cells grown in spheroid cultures, which resemble those found in tumour tissue. We also found that SCD mRNA and protein expression is elevated in human breast cancers and predicts poor survival in high-grade tumours. Finally, silencing of SCD in prostate orthografts efficiently blocked tumour growth and significantly increased animal survival.

Conclusions
Our data implicate lipid desaturation as an essential process for cancer cell survival and suggest that targeting SCD could efficiently limit tumour expansion, especially under the metabolically compromised conditions of the tumour microenvironment.
KW  - SCD
KW  - lipidomics
KW  - prostate cancer
KW  - breast cancer
KW  - lipid desaturation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145905
VL  - 4
IS  - 6
ER  - 
TY  - JOUR
A1  - Shemer, Yuval
A1  - Mekies, Lucy N.
A1  - Ben Jehuda, Ronen
A1  - Baskin, Polina
A1  - Shulman, Rita
A1  - Eisen, Binyamin
A1  - Regev, Danielle
A1  - Arbustini, Eloisa
A1  - Gerull, Brenda
A1  - Gherghiceanu, Mihaela
A1  - Gottlieb, Eyal
A1  - Arad, Michael
A1  - Binah, Ofer
T1  - Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes
JF  - International Journal of Molecular Sciences
N2  - LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients' induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I\(_f\)) density; (2) prolonged action potential duration and increased L-type Ca\(^{2+}\) current (I\(_{Ca,L}\)) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na\(^+\)/Ca\(^{2+}\) exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.
KW  - LMNA
KW  - dilated cardiomyopathy
KW  - iPSC-CMs
KW  - electrophysiology
KW  - arrhythmia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285673
SN  - 1422-0067
VL  - 22
IS  - 15
ER  -