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 26:84-103.|
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 Her2high disease.
We demonstrate that Her2high 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 Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory supercomplexes in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high 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, Human breast cancer MCF7 cells
Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology Pathology: Cancer Stress:Oxidative stress;RONS Organism: Human, Mouse Tissue;cell: Liver, Genital, Other cell lines Preparation: Permeabilized cells, Homogenate Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Supercomplex
Coupling state: LEAK, ROUTINE, ET Pathway: N, S, Other combinations HRR: Oxygraph-2k