AIMS: 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 (ETC) is a viable strategy to eliminate Her2high disease. RESULTS: We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs 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. INNOVATION: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. CONCLUSION: We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84-103.
AIMS: 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 (ETC) is a viable strategy to eliminate Her2high disease. RESULTS: We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs 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. INNOVATION: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. CONCLUSION: We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84-103.
Entities:
Keywords:
HER2; breast cancer; mitochondria; mitochondrially targeted tamoxifen; respirasome
Authors: J Neuzil; T Weber; A Schröder; M Lu; G Ostermann; N Gellert; G C Mayne; B Olejnicka; A Nègre-Salvayre; M Stícha; R J Coffey; C Weber Journal: FASEB J Date: 2001-02 Impact factor: 5.191
Authors: Lan-Feng Dong; Victoria J A Jameson; David Tilly; Jiri Cerny; Elahe Mahdavian; Alvaro Marín-Hernández; Luz Hernández-Esquivel; Sara Rodríguez-Enríquez; Jan Stursa; Paul K Witting; Bela Stantic; Jakub Rohlena; Jaroslav Truksa; Katarina Kluckova; Jeffrey C Dyason; Miroslav Ledvina; Brian A Salvatore; Rafael Moreno-Sánchez; Mark J Coster; Stephen J Ralph; Robin A J Smith; Jiri Neuzil Journal: J Biol Chem Date: 2010-11-08 Impact factor: 5.157
Authors: Frank Weinberg; Robert Hamanaka; William W Wheaton; Samuel Weinberg; Joy Joseph; Marcos Lopez; Balaraman Kalyanaraman; Gökhan M Mutlu; G R Scott Budinger; Navdeep S Chandel Journal: Proc Natl Acad Sci U S A Date: 2010-04-26 Impact factor: 11.205
Authors: Lubomir Prochazka; Stepan Koudelka; Lan-Feng Dong; Jan Stursa; Jacob Goodwin; Jiri Neca; Josef Slavik; Miroslav Ciganek; Josef Masek; Katarina Kluckova; Maria Nguyen; Jaroslav Turanek; Jiri Neuzil Journal: Apoptosis Date: 2013-03 Impact factor: 4.677
Authors: L-F Dong; P Low; J C Dyason; X-F Wang; L Prochazka; P K Witting; R Freeman; E Swettenham; K Valis; J Liu; R Zobalova; J Turanek; D R Spitz; F E Domann; I E Scheffler; S J Ralph; J Neuzil Journal: Oncogene Date: 2008-03-31 Impact factor: 9.867
Authors: Martina Bajzikova; Jaromira Kovarova; Ana R Coelho; Stepana Boukalova; Sehyun Oh; Katerina Rohlenova; David Svec; Sona Hubackova; Berwini Endaya; Kristyna Judasova; Ayenachew Bezawork-Geleta; Katarina Kluckova; Laurent Chatre; Renata Zobalova; Anna Novakova; Katerina Vanova; Zuzana Ezrova; Ghassan J Maghzal; Silvia Magalhaes Novais; Marie Olsinova; Linda Krobova; Yong Jin An; Eliska Davidova; Zuzana Nahacka; Margarita Sobol; Teresa Cunha-Oliveira; Cristian Sandoval-Acuña; Hynek Strnad; Tongchuan Zhang; Thanh Huynh; Teresa L Serafim; Pavel Hozak; Vilma A Sardao; Werner J H Koopman; Miria Ricchetti; Paulo J Oliveira; Frantisek Kolar; Mikael Kubista; Jaroslav Truksa; Katerina Dvorakova-Hortova; Karel Pacak; Robert Gurlich; Roland Stocker; Yaoqi Zhou; Michael V Berridge; Sunghyouk Park; Lanfeng Dong; Jakub Rohlena; Jiri Neuzil Journal: Cell Metab Date: 2018-11-15 Impact factor: 27.287
Authors: Dennis Ma; Christopher Pignanelli; Daniel Tarade; Tyler Gilbert; Megan Noel; Fadi Mansour; Scott Adams; Alexander Dowhayko; Kyle Stokes; Sergey Vshyvenko; Tomas Hudlicky; James McNulty; Siyaram Pandey Journal: Sci Rep Date: 2017-02-21 Impact factor: 4.379