bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2022–05–29
two papers selected by
Laia Caja Puigsubira, Uppsala University
  1. Breast cancer chemotherapy induces vascular dysfunction and hypertension through NOX4 dependent mechanism.
  2. NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway.
  1. J Clin Invest. 2022 May 26. pii: e149117. [Epub ahead of print]
    Breast cancer chemotherapy induces vascular dysfunction and hypertension through NOX4 dependent mechanism.
    Piotr Szczepaniak, Mateusz Siedlinski, Diana Hodorowicz-Zaniewska, Ryszard Nosalski, Tomasz P Mikolajczyk, Aneta M Dobosz, Anna Dikalova, Sergey Dikalov, Joanna Streb, Katarzyna Gara, Pawel Basta, Jaroslaw Krolczyk, Joanna Sulicka-Grodzicka, Ewelina Jozefczuk, Anna Dziewulska, Blessy Saju, Iwona Laksa, Wei Chen, John Dormer, Maciej Tomaszewski, Pasquale Maffia, Marta Czesnikiewicz-Guzik, Filippo Crea, Agnieszka Dobrzyn, Javid Moslehi, Tomasz Grodzicki, David G Harrison, Tomasz J Guzik.
      Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets.We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin and cyclophosphamide (NACT), and women with no history of such treatment matched for key clinical parameters. Mechanisms were explored in wild-type and Nox4-/- mice and human microvascular endothelial cells.Endothelium-dependent vasodilatation is severely impaired in patients after NACT, while endothelium-independent responses remain normal. This was mimicked by 24-hour exposure of arteries to NACT agents ex-vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a ROCK-dependent manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice. These were prevented in Nox4-/- and by pharmacological inhibition of Nox4 or Rock.Commonly used chemotherapeutic agents, and in particular, docetaxel, alter vascular function by promoting inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.
    Keywords:  Breast cancer; Cardiovascular disease; Molecular biology; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI149117
  2. J Nanobiotechnology. 2022 May 23. 20(1): 241
    NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway.
    Wei Wang, Xiaolong Liang, Xin Liu, Jiaxiang Bai, Wei Zhang, Wenming Li, Tianhao Wang, Meng Li, Zerui Wu, Liang Chen, Huilin Yang, Ye Gu, Yunxia Tao, Jun Zhou, Huaiyu Wang, Dechun Geng.
      Periprosthetic osteolysis (PPO) triggered by wear particles is the most severe complication of total joint replacement (TJR) surgeries, representing the major cause of implant failure, which is public health concern worldwide. Previous studies have confirmed the specialized role of osteoclast-induced progressive bone destruction in the progression of PPO. Additionally, the reactive oxygen species (ROS) induced by wear particles can promote excessive osteoclastogenesis and bone resorption. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a cellular enzyme, is considered to be responsible for the production of ROS and the formation of mature osteoclasts. However, NOX4 involvement in PPO has not yet been elucidated. Therefore, we investigated the mechanism by which NOX4 regulates osteoclast differentiation and the therapeutic effects on titanium nanoparticle-induced bone destruction. We found that NOX4 blockade suppressed osteoclastogenesis and enhanced the scavenging of intracellular ROS. Our rescue experiment revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) silencing reversed the effects of NOX4 blockade on ROS production and osteoclast differentiation. In addition, we found increased expression levels of NOX4 in PPO tissues, while NOX4 inhibition in vivo exerted protective effects on titanium nanoparticle-induced osteolysis through antiosteoclastic and antioxidant effects. Collectively, these findings suggested that NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway and that NOX4 blockade may be an attractive therapeutic approach for preventing PPO.
    Keywords:  NOX4; Nrf2; Osteoclastogenesis; Periprosthetic osteolysis; Titanium nanoparticles
    DOI:  https://doi.org/10.1186/s12951-022-01413-w
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