image: Genes upregulated in aging which are targeted by miRNAs from Meg3-Mirg locus. DNMT2/TRDMT1 gene knockout modulated DOX- and ETOPO-induced senescence program in glioblastoma cells as judged by affected SIPS response (lowered number of SA-beta-gal-positive cells and diminished levels of nuclear p21), apoptosis resistance, increased ROS production, increased DSBs, impaired RNA-mediated DDR and autophagic response, modulated SASP and the levels of NSUN proteins. Thus, DNMT2/TRDMT1 gene knockout may result in the promotion of some selected adverse side effects mediated by drug-stimulated senescence. view more
Credit: Correspondence to: Anna Lewinska email: lewinska@ur.edu.pl and Maciej Wnuk email: mwnuk@ur.edu.pl
Aging-US published "The lack of functional DNMT2/TRDMT1 gene modulates cancer cell responses during drug-induced senescence" which reported that cellular senescence may be a side effect of chemotherapy and other anti-cancer treatments that may promote inflammation and paracrine secondary senescence in healthy tissues.
DNMT2/TRDMT1 methyltransferase is implicated in the regulation of cellular lifespan and DNA damage response.
In this Aging-US study, the responses to senescence inducing concentrations of doxorubicin and etoposide in different cancer cells with DNMT2/TRDMT1 gene knockout were evaluated, namely changes in the cell cycle, apoptosis, autophagy, interleukin levels, genetic stability and DDR, and 5-mC and NSUN1-6 levels.
Diverse responses were revealed that were based on type of cancer cells and anti-cancer drugs.
DNMT2/TRDMT1 gene knockout in drug-treated glioblastoma cells resulted in decreased number of apoptotic and senescent cells, IL-8 levels and autophagy, and increased number of necrotic cells, DNA damage and affected DDR compared to drug-treated glioblastoma cells with unmodified levels of DNMT2/TRDMT1.
The authors suggest that DNMT2/TRDMT1 gene knockout in selected experimental settings may potentiate some adverse effects associated with chemotherapy-induced senescence.
Dr. Anna Lewinska and Dr. Maciej Wnuk from The University of Rzeszow said, "A number of anti-cancer strategies, which are based on chemotherapy, radiotherapy and immunotherapy or the use of CDK4/6 inhibitors and epigenetic modulators may promote cellular senescence in cancer and normal cells and tissues as an adverse side effect."
Moreover, therapy-induced senescence in cancer cells is no longer considered functionally irreversible as senescent cancer cells may escape from growth arrest, resume proliferation and exhibit more invasive and migratory properties than untreated corresponding cancer cells, which in turn may drive the formation of secondary tumors or cancer relapse.
Thus, the elimination of cancer-associated senescent cells both cancer cells and normal cells by senolytic drugs and the attenuation of SASP by senostatics seem a new promising approach to prevent or delay cancer recurrence and relieve frailty and multimorbidity in long-term cancer survivors.
It was suggested that DNMT2/TRDMT1 might be considered as a novel target in cancer therapy as the loss of DNMT2/TRDMT1 sensitized cancer cells to PARP inhibitors in vitro and in vivo.
In the present study, the authors have used four different cancer cell types to analyze the effects of DNMT2/TRDMT1 gene knockout during doxorubicin- and etoposide-induced senescence and the impact of AZA post-treatment.
Detailed consequences of the lack of functional DNMT2/TRDMT1 gene during drug-mediated senescence in four human cancer cell lines are presented and discussed.
The Lewinska/Wnuk Research Team concluded in their Aging-US Research Output, "we have shown for the first time that DNMT2/TRDMT1 gene knockout affected DOX- and ETOPO-mediated senescence program in glioblastoma cells as judged by modulated SIPS response (decreased number of SA-beta-gal-positive cells and nuclear p21 pools), apoptosis resistance, increased ROS levels, elevated DNA damage and impaired RNA-mediated DDR, limited autophagic response, modulated SASP and affected NSUN levels."
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DOI - https://doi.org/10.18632/aging.203203
Full Text - https://www.aging-us.com/article/203203/text
Correspondence to: Anna Lewinska email: lewinska@ur.edu.pl and Maciej Wnuk email: mwnuk@ur.edu.pl
Keywords: DNMT2/TRDMT1, cancer cells, anti-cancer drugs, chemotherapy-induced senescence
About Aging-US
Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.
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Aging-US
Article Title
The lack of functional DNMT2/TRDMT1 gene modulates cancer cell responses during drug-induced senescence