Rohlenova 2016 Antioxid Redox Signal

Rohlenova K, Sachaphibulkij K, Stursa J, Bezawork-Geleta A, Blecha J, Endaya B, Werner L, Cerny J, Zobalova R, Goodwin J, Spacek T, Alisadeh E, Yan B, Nguyen M, Vondrusova M, Sobol M, Jezek P, Hozak P, Truksa J, Rohlena J, Dong L, Neuzil J (2016) Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2high breast cancer. Antioxid Redox Signal [Epub ahead of print].

» PMID: 27392540

Rohlenova K, Sachaphibulkij K, Stursa J, Bezawork-Geleta A, Blecha J, Endaya B, Werner L, Cerny J, Zobalova R, Goodwin J, Spacek T, Alisadeh E, Yan B, Nguyen M, Vondrusova M, Sobol M, Jezek P, Hozak P, Truksa J, Rohlena J, Dong L, Neuzil J (2016) Antioxid Redox Signal

Abstract: Expression of the Her2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain is a viable strategy to eliminate Her2^high disease.

We demonstrate that Her2^high cells and tumors have increased assembly of respiratory supercomplexes and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondria-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently eradicates experimental Her2^high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory supercomplexes in Her2^high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2^high cells to MitoTam is dependent on the mitochondrial fraction of Her2.

Oncogenes such as Her2 can restructure electron transport chain, creating a previously unrecognized therapeutic vulnerability exploitable by supercomplex-disrupting agents such as MitoTam.

We propose that the electron transport chain is a suitable therapeutic target in Her2-high disease. • Keywords: Electron transport chain, Supercomplexes, Tamoxifen, Complex I, Her2

• O2k-Network Lab: CZ Prague Jezek P, AU Queensland Neuzil J, CZ Prague Jezek P, AU Queensland Peart J, CZ Prague Neuzil J

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer  Stress:Oxidative stress;RONS  Organism: Mouse 

Preparation: Permeabilized cells  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Supercomplex 

Coupling state: LEAK, ROUTINE, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property. 

HRR: Oxygraph-2k 

Labels, 2016-07