NOX4 Signaling Mediates Cancer Development and Therapeutic Resistance through HER3 in Ovarian Cancer Cells

Abstract

Development of resistance to therapy in ovarian cancer is a major hinderance for therapeutic efficacy; however, new mechanisms of the resistance remain to be elucidated. NADPH oxidase 4 (NOX4) is responsible for higher NADPH activity to increase reactive oxygen species (ROS) production. In this study, we showed that higher levels of NOX4 were detected in a large portion of human ovarian cancer samples. To understand the molecular mechanism of the NOX4 upregulation, we showed that NOX4 expression was induced by HIF-1α and growth factor such as IGF-1. Furthermore, our results indicated that NOX4 played a pivotal role in chemotherapy and radiotherapy resistance in ovarian cancer cells. We also demonstrated that NOX4 knockdown increased sensitivity of targeted therapy and radiotherapy through decreased expression of HER3 (ERBB3) and NF-κB p65. Taken together, we identified a new HIF-1α/NOX4 signal pathway which induced drug and radiation resistance in ovarian cancer. The finding may provide a new option to overcome the therapeutic resistance of ovarian cancer in the future.

NADPH Oxidase 4: A Potential Therapeutic Target of Malignancy

“…NOX4 also participates in the regulation of other cancer types, including prostate cancer, gallbladder cancer, thyroid cancer, and ovarian cancer ( Sampson et al, 2018 ; Helfinger et al, 2019 ; Pan et al, 2020 ; Liu et al, 2021 ). In human prostate cancer, NOX4 mediates TGFβ1-induced activation of primary fibroblasts to acquire a CAF-associated phenotype.…”

“…NOX4 also mediates the resistance to chemotherapy and radiotherapy in ovarian cancer cells. NOX4 blockade could significantly elevate response of A2780 and OVCAR3 cells to chemotherapy and radiotherapy by downregulating HER3 and NF-κB p65 ( Liu et al, 2021 ). Taken together, NOX4 displays great significance in wide variety of cancers, indicating great potentials of NOX4 inhibitors as anti-tumor therapy.…”

“…Numerous studies have shown that NOX4 plays a crucial role in tumorigenesis and tumor development by supporting cancer cell transformation, proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). To date, NOX4 has been observed to participate in multiple malignancies, including lung cancer, renal cell cancer (RCC), colorectal cancer (CRC), gastric cancer (GC), pancreatic cancer, glioblastoma, and ovarian cancer, etc ( Zeng et al, 2016 ; Meitzler et al, 2017 ; Shanmugasundaram et al, 2017 ; Du et al, 2018 ; Liu et al, 2021 ; Shen et al, 2020 ).…”

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

“…NOX4 is also highly expressed in non-small cell lung cancer (NSCLC) and promotes cancer progression by inducing glycolysis during c-Myc activation via the ROS/PI3K/Akt pathway, while GKT137831, a selective NOX4 inhibitor, suppresses the growth of tumor cells both in vitro and in vivo [ 101 ]. The high NOX4 expression predicted the worst clinical outcome in terms of overall survival in patients with endometrial [ 102 ] and ovarian cancer [ 103 ]. In addition, the knockdown of this gene in ovarian cancer cells has increased the sensitivity to chemo- and radiotherapy, which suggests a key role of NOX4 in the development of drug resistance.…”

The Role of the BH4 Cofactor in Nitric Oxide Synthase Activity and Cancer Progression: Two Sides of the Same Coin

“…Surprisingly, sepiapterin increased migration and proliferation of ovarian cancer cells in the absence of growth factors, which is mediated by a NO-dependent activation of ERK, AKT, and p70S6K signaling [68]. Since VGFR2 activation promotes ROS increase which is associated with ovarian cancer development [159][160][161], impairment of cell growth in the presence of sepiapterin can be attributed to NOS recoupling. These results suggest that the role of sepiapterin in cancer is related to the modulation of signaling pathways by NO or ROS.…”