Telomerase inhibitors induce mitochondrial oxidation and DNA damage-dependent cell death rescued by Bcl-2/Bcl-xL.

Autor: Jayaprasad AG; Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India; PhD Program, Manipal Academy of Higher Education (MAHE), Madhav Nagar, Manipal, Karnataka 576104, India., Chandrasekharan A; Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India., Arun Jyothi SP; Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India., John Sam SM; Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India., Santhoshkumar TR; Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India. Electronic address: trsanthosh@rgcb.res.in., Pillai MR; Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojappura, Thycaud, Thiruvananthapuram 695014, Kerala, India. Electronic address: mrpillai@gmail.com.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Apr; Vol. 264 (Pt 1), pp. 130151. Date of Electronic Publication: 2024 Feb 24.
DOI: 10.1016/j.ijbiomac.2024.130151
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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