Selective Elimination of Senescent Cells by Mitochondrial Targeting is Regulated by ANT2

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2018 May 23

PMID 29786070

Citations 37

Authors

Sona Hubackova

Eliska Davidova

Katerina Rohlenova

Jan Stursa

Lukas Werner

Ladislav Andera

Lanfeng Dong

Mikkel G Terp

Zdenek Hodny

Henrik J Ditzel

Jakub Rohlena

Jiri Neuzil

Affiliations

Soon will be listed here.

Abstract

Cellular senescence is a form of cell cycle arrest that limits the proliferative potential of cells, including tumour cells. However, inability of immune cells to subsequently eliminate senescent cells from the organism may lead to tissue damage, inflammation, enhanced carcinogenesis and development of age-related diseases. We found that the anticancer agent mitochondria-targeted tamoxifen (MitoTam), unlike conventional anticancer agents, kills cancer cells without inducing senescence in vitro and in vivo. Surprisingly, it also selectively eliminates both malignant and non-cancerous senescent cells. In naturally aged mice treated with MitoTam for 4 weeks, we observed a significant decrease of senescence markers in all tested organs compared to non-treated animals. Mechanistically, we found that the susceptibility of senescent cells to MitoTam is linked to a very low expression level of adenine nucleotide translocase-2 (ANT2), inherent to the senescent phenotype. Restoration of ANT2 in senescent cells resulted in resistance to MitoTam, while its downregulation in non-senescent cells promoted their MitoTam-triggered elimination. Our study documents a novel, translationally intriguing role for an anticancer agent targeting mitochondria, that may result in a new strategy for the treatment of age-related diseases and senescence-associated pathologies.

Citing Articles

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The dual role of cellular senescence in human tumor progression and therapy.

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A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity.

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References

Braig M, Lee S, Loddenkemper C, Rudolph C, Peters A, Schlegelberger B . Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005; 436(7051):660-5. DOI: 10.1038/nature03841. View

Michaloglou C, Vredeveld L, Soengas M, Denoyelle C, Kuilman T, van der Horst C . BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005; 436(7051):720-4. DOI: 10.1038/nature03890. View

Munoz-Espin D, Serrano M . Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014; 15(7):482-96. DOI: 10.1038/nrm3823. View

Sabin R, Anderson R . Cellular Senescence - its role in cancer and the response to ionizing radiation. Genome Integr. 2011; 2(1):7. PMC: 3169443. DOI: 10.1186/2041-9414-2-7. View

Kuilman T, Michaloglou C, Vredeveld L, Douma S, van Doorn R, Desmet C . Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008; 133(6):1019-31. DOI: 10.1016/j.cell.2008.03.039. View

Moiseeva O, Mallette F, Mukhopadhyay U, Moores A, Ferbeyre G . DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell. 2006; 17(4):1583-92. PMC: 1415317. DOI: 10.1091/mbc.e05-09-0858. View

Coppe J, Desprez P, Krtolica A, Campisi J . The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99-118. PMC: 4166495. DOI: 10.1146/annurev-pathol-121808-102144. View

Carlos Acosta J, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton J . A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013; 15(8):978-90. PMC: 3732483. DOI: 10.1038/ncb2784. View

Hubackova S, Kucerova A, Michlits G, Kyjacova L, Reinis M, Korolov O . IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2. Oncogene. 2015; 35(10):1236-49. DOI: 10.1038/onc.2015.162. View

10.

Hubackova S, Krejcikova K, Bartek J, Hodny Z . IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'bystander senescence'. Aging (Albany NY). 2013; 4(12):932-51. PMC: 3615160. DOI: 10.18632/aging.100520. View

11.

Baker D, Wijshake T, Tchkonia T, LeBrasseur N, Childs B, van de Sluis B . Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479(7372):232-6. PMC: 3468323. DOI: 10.1038/nature10600. View

12.

Baker D, Childs B, Durik M, Wijers M, Sieben C, Zhong J . Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016; 530(7589):184-9. PMC: 4845101. DOI: 10.1038/nature16932. View

13.

Sone H, Kagawa Y . Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia. 2004; 48(1):58-67. DOI: 10.1007/s00125-004-1605-2. View

14.

Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T . A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med. 2009; 15(9):1082-7. DOI: 10.1038/nm.2014. View

15.

Tchkonia T, Morbeck D, von Zglinicki T, van Deursen J, Lustgarten J, Scrable H . Fat tissue, aging, and cellular senescence. Aging Cell. 2010; 9(5):667-84. PMC: 2941545. DOI: 10.1111/j.1474-9726.2010.00608.x. View

16.

Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I . Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002; 105(13):1541-4. DOI: 10.1161/01.cir.0000013836.85741.17. View

17.

Demaria M, OLeary M, Chang J, Shao L, Liu S, Alimirah F . Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2016; 7(2):165-176. PMC: 5296251. DOI: 10.1158/2159-8290.CD-16-0241. View

18.

Dorr J, Yu Y, Milanovic M, Beuster G, Zasada C, Dabritz J . Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature. 2013; 501(7467):421-5. DOI: 10.1038/nature12437. View

19.

Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov V, Mackay G . A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature. 2013; 498(7452):109-12. DOI: 10.1038/nature12154. View

20.

St-Pierre J, Drori S, Uldry M, Silvaggi J, Rhee J, Jager S . Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006; 127(2):397-408. DOI: 10.1016/j.cell.2006.09.024. View