Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients
نویسندگان
چکیده
Anti-cancer drugs often increase reactive oxygen species (ROS) and cause DNA damage. Here, we highlight a new cross talk between chronic oxidative stress and the histone variant H2AX, a key player in DNA repair. We observe that persistent accumulation of ROS, due to a deficient JunD-/Nrf2-antioxidant response, reduces H2AX protein levels. This effect is mediated by an enhanced interaction of H2AX with the E3 ubiquitin ligase RNF168, which is associated with H2AX poly-ubiquitination and promotes its degradation by the proteasome. ROS-mediated H2AX decrease plays a crucial role in chemosensitivity. Indeed, cycles of chemotherapy that sustainably increase ROS reduce H2AX protein levels in Triple-Negative breast cancer (TNBC) patients. H2AX decrease by such treatment is associated with an impaired NRF2-antioxidant response and is indicative of the therapeutic efficiency and survival of TNBC patients. Thus, our data describe a novel ROS-mediated regulation of H2AX turnover, which provides new insights into genetic instability and treatment efficacy in TNBC patients.
منابع مشابه
Three cycles of AC chemotherapy regimen increased oxidative stress in breast cancer patients: A clinical hint
Background: Recent studies have suggested the importance of oxidant/antioxidant status in initiation and progression of breast cancer. The aim of this study was to evaluate oxidative stress markers in breast cancer patients before and after 3 cycles of chemotherapy with adriamycin and cytoxan (AC). Also, in this study the effect of age and the stage of disease on oxidative stress markers were c...
متن کاملThe nuclear matrix protein, NRP/B, enhances Nrf2-mediated oxidative stress responses in breast cancer cells.
The transcription factor NF-E2-related factor 2 (Nrf2) translocates into the nucleus and activates phase II genes encoding detoxification enzymes and antioxidant proteins, resulting in the protection of cells from oxidative insults. However, the involvement of Nrf2-mediated oxidative stress responses in breast cancer cells is largely unknown. Notably, during our study of the Nrf2 pathway in bre...
متن کاملEnhanced Radiosensitivity and Chemosensitivity of Breast Cancer Cells by 2-Deoxy-D-Glucose in Combination Therapy
Breast cancer is the most common malignancy, and it is also the major cause of cancer-related deaths of women worldwide. Breast cancer treatment involves surgery, chemotherapy, radiation therapy, or combination therapy, and novel strategies are needed to boost the oncologic outcome. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) which inhibits glucose synthesis and adenosine t...
متن کاملγ-H2AX as a protein biomarker for radiation exposure response in ductal carcinoma breast tumors: Experimental evidence and literature review
Background: H2AX is a histone variant that is systematically found and ubiquitously distributed throughout the genome. DNA double-strand breaks (DSBs) induce phosphorylation of H2AX at serine 139 (γH2AX), an immunocytochemical assay with antibodies recognizing γH2AX has become the gold standard for the detection of DSBs. The importance of this assay to investigate different individu...
متن کاملEffect of written Exposure Therapy (WET) Vs Mindfulness-Based Stress Reduction(MBSR) on Post-Traumatic Stress Symptoms and Fear of Recurrence in Patients with Breast Cancer
Introduction: Breast cancer (BC) is the most common cancer diagnosed in women in Worldwide.A breast cancer diagnosis can be a life-changing and stressful experience that can lead to chronic mental health conditions such as posttraumatic stress disorder (PTSD) and fear of cancer recurrence(FCR). This study examined the effect of written exposure therapy and mindfulness-based stress reduction on...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 8 شماره
صفحات -
تاریخ انتشار 2016