التفاصيل البيبلوغرافية
| العنوان: |
Telomerase inhibitors induce mitochondrial oxidation and DNA damage-dependent cell death rescued by Bcl-2/Bcl-xL. |
| المؤلفون: |
Jayaprasad, Aparna Geetha1,2 (AUTHOR), Chandrasekharan, Aneesh1 (AUTHOR), Arun Jyothi, S.P.1 (AUTHOR), John Sam, S.M.1 (AUTHOR), Santhoshkumar, T.R.1 (AUTHOR) trsanthosh@rgcb.res.in, Pillai, M. Radhakrishna1 (AUTHOR) mrpillai@gmail.com |
| المصدر: |
International Journal of Biological Macromolecules. Apr2024:Part 1, Vol. 264, pN.PAG-N.PAG. 1p. |
| مصطلحات موضوعية: |
*MITOCHONDRIAL DNA, *TELOMERASE, *CELL death, *MEMBRANE potential, *CELLULAR aging, *BCL-2 proteins, *CELL survival, *DNA damage |
| مستخلص: |
Reactivation of telomerase is a hallmark of cancer and the majority of cancers over-express telomerase. Telomerase-dependent telomere length maintenance confers immortality to cancer cells. However, telomere length-independent cell survival functions of telomerase also play a critical role in tumorigenesis. Multiple telomerase inhibitors have been developed as therapeutics and include anti-sense oligonucleotides, telomerase RNA component targeting agents, chemical inhibitors of telomerase, small molecule inhibitors of hTERT, and telomerase vaccine. In general, telomerase inhibitors affect cell proliferation and survival of cells depending on the telomere length reduction, culminating in replicative senescence or cell death by crisis. However, most telomerase inhibitors kill cancer cells prior to significant reduction in telomere length, suggesting telomere length independent role of telomerase in early telomere dysfunction-dependent cell death. In this study, we explored the mechanism of cell death induced by three prominent telomerase inhibitors utilizing a series of genetically encoded sensor cells including redox and DNA damage sensor cells. We report that telomerase inhibitors induce early cell cycle inhibition, followed by redox alterations at cytosol and mitochondria. Massive mitochondrial oxidation and DNA damage induce classical cell death involving mitochondrial transmembrane potential loss and mitochondrial permeabilization. Real-time imaging of the progression of mitochondrial oxidation revealed that treated cells undergo a biphasic mitochondrial redox alteration during telomerase inhibition, emphasizing the potential role of telomerase in the redox regulation at mitochondria. Additionally, silencing of hTERT confirmed its predominant role in maintaining mitochondrial redox homeostasis. Interestingly, the study also demonstrated that anti-apoptotic Bcl-2 family proteins still confer protection against cell death induced by telomerase inhibitors. The study demonstrates that redox alterations and DNA damage contribute to early cell death by telomerase inhibitors and anti-apoptotic Bcl-2 family proteins confer protection from cell death by their ability to safeguard mitochondria from oxidation damage. • Real-time imaging revealed that telomerase inhibitors induce mitochondrial ROS-dependent mitochondrial permeabilization. • Telomerase inhibition causes redox alterations and DNA damage, contributing to early cell death. • Silencing of Telomerase also induces mitochondrial and cytosolic ROS generation. • Bcl-2 family proteins confer protection against cell death and mitochondrial oxidation induced by telomerase inhibitors. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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