Silencing BMI1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy

Abstract

Overexpression of BMI1 in human cancer cells, a member of the polycomb group of repressive complexes, correlates with advanced stage of disease, aggressive clinico-pathological behavior, poor prognosis, and resistance to radiation and chemotherapy. Studies have shown that experimental reduction of BMI1 protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increased susceptibility to cytotoxic agents and radiation therapy. Although a role for BMI1 in cancer progression and its importance as a molecular target for cancer therapy has been established, information on the impact of silencing BMI1 in triple-negative breast cancer (TNBC) and its consequence on radiotherapy have not been well studied. Therefore, in the present study we investigated the potential therapeutic benefit of radiation therapy in BMI1-silenced breast cancer cells and studied the mechanism(s) of radiosensitization. Human MDA-MB-231 and SUM159PT breast cancer cells that were either stably transfected with a lentiviral vector expressing BMI1 shRNA (shBMI1) or control shRNA (shControl) or transient transfection with a BMI1-specific siRNA were used. Silencing of BMI1 resulted in marked reduction in BMI1 both at the mRNA and protein level that was accompanied by a significant reduction in cell migration compared to control cells. Further, BMI1 knockdown produced a marked enhancement of DNA damage as evidenced by Comet Assay and γH2AX foci, resulting in a dose-dependent radiosensitization effect. Molecular studies revealed modulation of protein expression that is associated with the DNA damage response (DDR) and autophagy pathways. Our results demonstrate that BMI1 is an important therapeutic target in breast cancer and suppression of BMI1 produces radiation sensitivity. Further, combining BMI1-targeted therapeutics with radiation might benefit patients diagnosed with TNBC.

Induction of apoptosis and ferroptosis by a tumor suppressing magnetic field through ROS-mediated DNA damage

“…On the other hand, increase of PARP suggested recognition and repair of DNA SSB through base excision repair (BER) [37]. In addition, the field seemed to be able to induce unconventional DNA repair pathways involving RAD9B [38] and BMI [39] genes. In our model, although DNA damage was pronounced following MF exposure, the activities of the multiple DNA repair mechanisms remain to be evaluated.…”

An Interplay between Senescence, Apoptosis and Autophagy in Glioblastoma Multiforme—Role in Pathogenesis and Therapeutic Perspective

“…It was reported that copper evoked premature senescence in the GBM U87-MG cells with concomitant downregulation of the BMI1 (proto-oncogene, polycomb ring finger, B lymphoma Mo-MLV insertion region 1 homolog (mouse)) pathway [ 62 ]. BMI1 was shown to be involved in autophagy regulation in several cancers, including chronic myeloid leukemia, breast and ovarian cancers [ 63 , 64 , 65 ]. Research performed on the GBM U87-MG cell line, both wild-type and p53-mutated, showed that arsenite evoked premature senescence as a result of DNA damage in a p53/p21-depedent fashion [ 66 ].…”

Myocardial Cell Aging in the Elderly

“…The Bmi-1 gene can prevent cell aging though inhibiting transcription of the p16Ink4a/ p19Arf signaling pathway [62]. In addition, Bmi-1 can also prevent DNA damage and delay aging by maintaining mitochondrial function and redox balance [63]. Recent research has confirmed that estrogen deficiency can not only reduce the levels of antioxidant enzymes such as SODl and SOD2 in the mouse heart, but also reduce the expression of SIRT1 and Bmi-1, all these changes can increase oxidative stress in cardiomyocytes and promote senescence and apoptosis of cardiomyocytes in ovariectomized mice [64].…”