The STAT-ROS cycle extends IFN‑induced cancer cell apoptosis

Abstract

In mammals, the signal transducer and activator of transcription (STAT) protein processes mitochondria importation targets and mitochondria respiratory complexes, and triggers reactive oxygen species (ROS) generation, which conversely rapidly initiates the activation of STAT. Interferon (IFN) administration increases cancer cell apoptosis via STAT activation and ROS accumulation. However, the existence of a STAT-ROS cycle and how it affects IFN-induced cancer cellular apoptosis are unclear. In the present study, we used MCF7 breast cancer cells and confirmed that a combination of IFN-α/β/γ incubation induced STAT1/3 phosphorylation and mitochondria importation, which increased mitochondria respiratory complexes, the cellular oxygen consumption rate (OCR), and ROS production, followed by cellular apoptosis. We also found that STAT1/3 overexpression induced mitochondria respiratory complexes and ROS production. Additionally, ROS induced by H 2 O 2 induced phosphorylation of STAT1/3 and promoted mitochondria importation. STAT1/3 deletion suppressed H 2 O 2-induced acute cellular OCR, increasing the ROS level and indicating that STAT1/3 is necessary for ROS-induced mitochondria OCR and further ROS production, suggesting the existence of a STAT-ROS cycle. We next found that IFN induced mitochondria respiratory complexes followed by induction of OCR, ROS, and apoptosis, which were partially blocked by STAT1/3 deletion. Additionally, the suppression of ROS inhibited IFN-induced STAT1/3 activation. Finally, we discovered that this cycle exists also in A431 and HeLa cancer cells. These results indicate that a STAT-ROS cycle extends IFN-induced cellular apoptosis.

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

“…29 In MCF-7 breast cancer cell line, H 2 O 2 has been reported to enhance the glutathionylation of STAT1, and promote IFN-induced apoptosis of tumor cells. 27 In line with these findings, we showed that in macrophages, Grx1 inhibited STAT1 activity through its thioltransferase activity during the process of M1-type polarization and suppressed the expression of the canonical inflammatory genes such as CXCL9.…”

“…Many studies have clarified the relationship between oxidative stress and STAT1 in different aspects. 27 Hypoxia-induced oxidative stress causes glutathionylation of STAT1 in the brain, which abnormally activates the STAT1 signaling pathway and promotes BV2 cells to transform into proinflammatory phenotype. 28 PACAP, which induces ROS, upregulates the phosphorylation level of STAT1.…”

Dectin-1 Promotes Type I and III Interferon Expression to Support Optimal Antifungal Immunity in the Lung

“…Dectin-1 is known to stimulate ROS production in response to zymosan via the Syk pathway (Gantner et al, 2003;Underhill et al, 2005). In addition, a link between STAT1 activation and ROS generation has been previously reported (Yamashita et al, 2013;Kim et al, 2017;Wang et al, 2018), suggesting that IFNs may also contribute to this process. Indeed, our own findings established that both type I and type III IFNs have critical roles in potentiating ROS production by neutrophils in response to pulmonary infection with Af (Espinosa et al, 2017).…”

Quantitative Proteomic Analysis Reveals That Arctigenin Alleviates Concanavalin A-Induced Hepatitis Through Suppressing Immune System and Regulating Autophagy

“…Transgenic mice overexpressing Stat1 showed elevated levels of IFN-γ and significantly aggravated liver injury after ConA administration, while Con A-induced liver injury hardly occurred in Stat1 −/− mice ( 13 ). This is due to Stat1-mediated upregulation of IFN-γ, which enhances the production of chemokines, adhesion molecules, and ROS ( 14 , 15 ). As reported, autophagy can facilitate IFN-γ-induced cellular inflammation via the activation of Jak2–Stat1 signaling ( 16 ).…”