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Activated SIRT1 contributes to DPT-induced glioma cell parthanatos by upregulation of NOX2 and NAT10

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Abstract

Parthanatos is a type of programmed cell death dependent on hyper-activation of poly (ADP-ribose) polymerase 1 (PARP-1). SIRT1 is a highly conserved nuclear deacetylase and often acts as an inhibitor of parthanatos by deacetylation of PARP1. Our previous study showed that deoxypodophyllotoxin (DPT), a natural compound isolated from the traditional herb Anthriscus sylvestris, triggered glioma cell death via parthanatos. In this study, we investigated the role of SIRT1 in DPT-induced human glioma cell parthanatos. We showed that DPT (450 nmol/L) activated both PARP1 and SIRT1, and induced parthanatos in U87 and U251 glioma cells. Activation of SIRT1 with SRT2183 (10 μmol/L) enhanced, while inhibition of SIRT1 with EX527 (200 μmol/L) or knockdown of SIRT1 attenuated DPT-induced PARP1 activation and glioma cell death. We demonstrated that DPT (450 nmol/L) significantly decreased intracellular NAD+ levels in U87 and U251 cells. Further decrease of NAD+ levels with FK866 (100 μmol/L) aggravated, but supplement of NAD+ (0.5, 2 mmol/L) attenuated DPT-induced PARP1 activation. We found that NAD+ depletion enhanced PARP1 activation via two ways: one was aggravating ROS-dependent DNA DSBs by upregulation of NADPH oxidase 2 (NOX2); the other was reinforcing PARP1 acetylation via increase of N-acetyltransferase 10 (NAT10) expression. We found that SIRT1 activity was improved when being phosphorylated by JNK at Ser27, the activated SIRT1 in reverse aggravated JNK activation via upregulating ROS-related ASK1 signaling, thus forming a positive feedback between JNK and SIRT1. Taken together, SIRT1 activated by JNK contributed to DPT-induced human glioma cell parthanatos via initiation of NAD+ depletion-dependent upregulation of NOX2 and NAT10.

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Fig. 1: SIRT1 activation boosted DPT-induced glioma cell parthanatos.
Fig. 2: SIRT1 activation enhanced DPT-induced DNA DSBs and PARP1 acetylation.
Fig. 3: SIRT1 activation reinforced DPT-induced NOX2 activation.
Fig. 4: SIRT1 activation reinforced DPT-induced NAT10 upregulation.
Fig. 5: NAD+ depletion contributed to DPT-induced upregulation of NAT10 and NOX2.
Fig. 6: JNK regulated DPT-induced SIRT1 activation.
Fig. 7: SIRT1-dependent NAD+ depletion reversely promoted DPT-induced JNK activation.
Fig. 8: DPT induced activation of PARP1 and SIRT1 in vivo.
Fig. 9: Schematic diagram of activated SIRT1 regulating glioma cell parthanatos induced by DPT.

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References

  1. Wang X, Ge P. Parthanatos in the pathogenesis of nervous system diseases. Neuroscience. 2020;449:241–50.

    Article  CAS  PubMed  Google Scholar 

  2. Alano CC, Garnier P, Ying W, Higashi Y, Kauppinen TM, Swanson RA. NAD+ depletion is necessary and sufficient for poly(ADP-ribose) polymerase-1-mediated neuronal death. J Neurosci. 2010;30:2967–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008;10:179–206.

    Article  CAS  PubMed  Google Scholar 

  4. Hou WH, Chen SH, Yu X. Poly-ADP ribosylation in DNA damage response and cancer therapy. Mutat Res Rev Mutat Res. 2019;780:82–91.

    Article  CAS  PubMed  Google Scholar 

  5. Ma D, Lu B, Feng C, Wang C, Wang Y, Luo T, et al. Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS. Cancer Lett. 2016;371:194–204.

    Article  CAS  PubMed  Google Scholar 

  6. Paul S, Jakhar R, Bhardwaj M, Chauhan AK, Kang SC. Fumonisin B1 induces poly (ADP-ribose) (PAR) polymer-mediated cell death (parthanatos) in neuroblastoma. Food Chem Toxicol. 2021;154:112326.

    Article  CAS  PubMed  Google Scholar 

  7. Li D, Kou Y, Gao Y, Liu S, Yang P, Hasegawa T, et al. Oxaliplatin induces the PARP1-mediated parthanatos in oral squamous cell carcinoma by increasing production of ROS. Aging. 2021;13:4242–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Luna A, Aladjem MI, Kohn KW. SIRT1/PARP1 crosstalk: connecting DNA damage and metabolism. Genome Integr. 2013;4:6.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Li C, Liu Z, Yang K, Chen X, Zeng Y, Liu J, et al. miR-133b inhibits glioma cell proliferation and invasion by targeting Sirt1. Oncotarget. 2016;7:36247–54.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chen H, Lin R, Zhang Z, Wei Q, Zhong Z, Huang J, et al. Sirtuin 1 knockdown inhibits glioma cell proliferation and potentiates temozolomide toxicity via facilitation of reactive oxygen species generation. Oncol Lett. 2019;17:5343–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Yao Z-Q, Zhang X, Zhen Y, He X-Y, Zhao S, Li X-F, et al. A novel small-molecule activator of Sirtuin-1 induces autophagic cell death/mitophagy as a potential therapeutic strategy in glioblastoma. Cell Death Dis. 2018;9:767.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lee Y-H, Chen H-Y, Su LJ, Chueh PJ. Sirtuin 1 (SIRT1) deacetylase activity and NAD+/NADH ratio are imperative for capsaicin-mediated programmed cell death. J Agric Food Chem. 2015;63:7361–70.

    Article  CAS  PubMed  Google Scholar 

  13. Zheng Z, Bian Y, Zhang Y, Ren G, Li G. Metformin activates AMPK/SIRT1/NF-kappaB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle. 2020;19:1089–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gerhart-Hines Z, Dominy JE Jr., Blattler SM, Jedrychowski MP, Banks AS, Lim JH, et al. The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD+. Mol Cell. 2011;44:851–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee Y-H, Kim S-J, Fang X, Song N-Y, Kim D-H, Suh J, et al. JNK-mediated Ser27 phosphorylation and stabilization of SIRT1 promote growth and progression of colon cancer through deacetylation-dependent activation of Snail. Mol Oncol. 2022;16:1555–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ford J, Ahmed S, Allison S, Jiang M, Milner J. JNK2-dependent regulation of SIRT1 protein stability. Cell Cycle. 2008;7:3091–7.

    Article  CAS  PubMed  Google Scholar 

  17. Nasrin N, Kaushik VK, Fortier E, Wall D, Pearson KJ, de Cabo R, et al. JNK1 phosphorylates SIRT1 and promotes its enzymatic activity. PLoS One. 2009;4:e8414.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xu Y, Wan W. Acetylation in the regulation of autophagy. Autophagy. 2023;19:379–87.

  19. Brown EE, Scandura MJ, Mehrotra S, Wang Y, Du J, Pierce EA. Reduced nuclear NAD+ drives DNA damage and subsequent immune activation in the retina. Hum Mol Genet. 2022;31:1370–88.

    Article  CAS  PubMed  Google Scholar 

  20. Murnyák B, Kouhsari MC, Hershkovitch R, Kálmán B, Marko-Varga G, Klekner Á, et al. PARP1 expression and its correlation with survival is tumour molecular subtype dependent in glioblastoma. Oncotarget. 2017;8:46348–62.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lu S, Wang XZ, He C, Wang L, Liang SP, Wang CC, et al. ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron. Acta Pharmacol Sin. 2021;42:1690–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhou Z, Lu B, Wang C, Wang Z, Luo T, Piao M, et al. RIP1 and RIP3 contribute to shikonin-induced DNA double-strand breaks in glioma cells via increase of intracellular reactive oxygen species. Cancer Lett. 2017;390:77–90.

    Article  PubMed  Google Scholar 

  23. He C, Lu S, Wang XZ, Wang CC, Wang L, Liang SP, et al. FOXO3a protects glioma cells against temozolomide-induced DNA double strand breaks via promotion of BNIP3-mediated mitophagy. Acta Pharmacol Sin. 2021;42:1324–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu S, Luo W, Wang Y. Emerging role of PARP-1 and PARthanatos in ischemic stroke. J Neurochem. 2022;160:74–87.

    Article  CAS  PubMed  Google Scholar 

  25. Vermot A, Petit-Hartlein I, Smith SME, Fieschi F. NADPH oxidases (NOX): an overview from discovery, molecular mechanisms to physiology and pathology. Antioxidants. 2021;10:890.

  26. Cheng F, Yuan W, Cao M, Chen R, Wu X, Yan J. Cyclophilin a protects cardiomyocytes against hypoxia/reoxygenation-induced apoptosis via the AKT/Nox2 pathway. Oxid Med Cell Longev. 2019;2019:2717986.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang Y, Ge X, Yu S, Cheng Q. Achyranthes bidentata polypeptide alleviates neurotoxicity of lipopolysaccharide-activated microglia via PI3K/Akt dependent NOX2/ROS pathway. Ann Transl Med. 2021;9:1522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hassa PO, Haenni SS, Buerki C, Meier NI, Lane WS, Owen H, et al. Acetylation of poly(ADP-ribose) polymerase-1 by p300/CREB-binding protein regulates coactivation of NF-kappaB-dependent transcription. J Biol Chem. 2005;280:40450–64.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang L, Li D-Q. MORC2 regulates DNA damage response through a PARP1-dependent pathway. Nucleic Acids Res. 2019;47:8502–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang ZX, Zhang WN, Sun YY, Li YH, Xu ZM, Fu WN. CREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis. Onco-Targets Ther. 2018;11:1323–31.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Huang M, Li X, Jia S, Liu S, Fu L, Jiang X, et al. Bisphenol AF induces apoptosis via estrogen receptor beta (ERbeta) and ROS-ASK1-JNK MAPK pathway in human granulosa cell line KGN. Environ Pollut. 2021;270:116051.

    Article  CAS  PubMed  Google Scholar 

  32. Ying W. NAD+ and NADH in cellular functions and cell death. Front Biosci. 2006;11:3129–48.

    Article  CAS  PubMed  Google Scholar 

  33. Alaee M, Khaghani S, Behroozfar K, Hesari Z, Ghorbanhosseini SS, Nourbakhsh M. Inhibition of nicotinamide phosphoribosyltransferase induces apoptosis in estrogen receptor-positive MCF-7 breast cancer cells. J Breast Cancer. 2017;20:20–6.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yang P, Zhang L, Shi QJ, Lu YB, Wu M, Wei EQ, et al. Nicotinamide phosphoribosyltransferase inhibitor APO866 induces C6 glioblastoma cell death via autophagy. Pharmazie. 2015;70:650–5.

    CAS  PubMed  Google Scholar 

  35. Pajuelo D, Gonzalez-Juarbe N, Tak U, Sun J, Orihuela CJ, Niederweis M. NAD+ depletion triggers macrophage necroptosis, a cell death pathway exploited by Mycobacterium tuberculosis. Cell Rep. 2018;24:429–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martínez-Morcillo FJ, Cantón-Sandoval J, Martínez-Navarro FJ, Cabas I, Martínez-Vicente I, Armistead J, et al. NAMPT-derived NAD+ fuels PARP1 to promote skin inflammation through parthanatos cell death. PLoS Biol. 2021;19:e3001455.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zheng T, Zheng CY, Zheng XC, Zhao RG, Chen YQ. Effect of parthanatos on ropivacaine-induced damage in SH-SY5Y cells. Clin Exp Pharmacol Physiol. 2017;44:586–94.

    Article  CAS  PubMed  Google Scholar 

  38. Lu P, Kamboj A, Gibson SB, Anderson CM. Poly(ADP-ribose) polymerase-1 causes mitochondrial damage and neuron death mediated by Bnip3. J Neurosci. 2014;34:15975–87.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ying W, Garnier P, Swanson RA. NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem Biophys Res Commun. 2003;308:809–13.

    Article  CAS  PubMed  Google Scholar 

  40. Carnevale I, Pellegrini L, D’Aquila P, Saladini S, Lococo E, Polletta L, et al. SIRT1-SIRT3 axis regulates cellular response to oxidative stress and etoposide. J Cell Physiol. 2017;232:1835–44.

    Article  CAS  PubMed  Google Scholar 

  41. Chai R, Fu H, Zheng Z, Liu T, Ji S, Li G. Resveratrol inhibits proliferation and migration through SIRT1 mediated post‑translational modification of PI3K/AKT signaling in hepatocellular carcinoma cells. Mol Med Rep. 2017;16:8037–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shi Z, Yao J, Ma X, Xu D, Ming G. CUL5-mediated visfatin (NAMPT) degradation blocks endothelial proliferation and angiogenesis via the MAPK/PI3K-AKT signaling. J Cardiovasc Pharmacol. 2021;78:891–9.

    Article  CAS  PubMed  Google Scholar 

  43. Vallejo FA, Sanchez A, Cuglievan B, Walters WM, De Angulo G, Vanni S, et al. NAMPT inhibition induces neuroblastoma cell death and blocks tumor growth. Front Oncol. 2022;12:883318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhao C, Li W, Duan H, Li Z, Jia Y, Zhang S, et al. NAD+ precursors protect corneal endothelial cells from UVB-induced apoptosis. Am J Physiol Cell Physiol. 2020;318:C796–C805.

    Article  CAS  PubMed  Google Scholar 

  45. Cao Y, Yao M, Wu Y, Ma N, Liu H, Zhang B. N-Acetyltransferase 10 promotes micronuclei formation to activate the senescence-associated secretory phenotype machinery in colorectal cancer cells. Transl Oncol. 2020;13:100783.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dalhat MH, Altayb HN, Khan MI, Choudhry H. Structural insights of human N-acetyltransferase 10 and identification of its potential novel inhibitors. Sci Rep. 2021;11:6051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang K, Zhou LY, Liu F, Lin L, Ju J, Tian PC, et al. PIWI-Interacting RNA HAAPIR regulates cardiomyocyte death after myocardial infarction by promoting NAT10-Mediated ac(4) C ACETYLATION Of Tfec mRNA. Adv Sci. 2022;9:e2106058.

    Article  Google Scholar 

  48. Liu H, Ling Y, Gong Y, Sun Y, Hou L, Zhang B. DNA damage induces N-acetyltransferase NAT10 gene expression through transcriptional activation. Mol Cell Biochem. 2007;300:249–58.

    Article  CAS  PubMed  Google Scholar 

  49. Jeong H, Cohen DE, Cui L, Supinski A, Savas JN, Mazzulli JR, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med. 2011;18:159–65.

    Article  PubMed  Google Scholar 

  50. Ma S, Yeom J, Lim YH. Exogenous NAD+ stimulates MUC2 expression in LS 174T goblet cells via the PLC-delta/PTGES/PKC-delta/ERK/CREB signaling pathway. Biomolecules. 2020;10:580.

  51. Kim YM, Park EJ, Kim HJ, Chang KC. Sirt1 S-nitrosylation induces acetylation of HMGB1 in LPS-activated RAW264.7 cells and endotoxemic mice. Biochem Biophys Res Commun. 2018;501:73–9.

    Article  CAS  PubMed  Google Scholar 

  52. Shinozaki S, Chang K, Sakai M, Shimizu N, Yamada M, Tanaka T, et al. Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65. Sci Signal. 2014;7:ra106.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sun HJ, Xiong SP, Cao X, Cao L, Zhu MY, Wu ZY, et al. Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-kappaB and STAT3. Redox Biol. 2021;38:101813.

    Article  CAS  PubMed  Google Scholar 

  54. Yu L, Dong L, Li H, Liu Z, Luo Z, Duan G, et al. Ubiquitination-mediated degradation of SIRT1 by SMURF2 suppresses CRC cell proliferation and tumorigenesis. Oncogene. 2020;39:4450–64.

    Article  CAS  PubMed  Google Scholar 

  55. Sasaki T, Maier B, Koclega KD, Chruszcz M, Gluba W, Stukenberg PT, et al. Phosphorylation regulates SIRT1 function. PLoS One. 2008;3:e4020.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lau AW, Liu P, Inuzuka H, Gao D. SIRT1 phosphorylation by AMP-activated protein kinase regulates p53 acetylation. Am J Cancer Res. 2014;4:245–55.

    PubMed  PubMed Central  Google Scholar 

  57. Kang H, Jung J-W, Kim MK, Chung JH. CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA damage. PLoS One. 2009;4:e6611.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chang CY, Pan PH, Wu CC, Liao SL, Chen WY, Kuan YH, et al. Endoplasmic reticulum stress contributes to gefitinib-induced apoptosis in glioma. Int J Mol Sci. 2021;22:3934.

  59. Zheng L, Wang C, Luo T, Lu B, Ma H, Zhou Z, et al. JNK activation contributes to oxidative stress-induced parthanatos in glioma cells via increase of intracellular ROS production. Mol Neurobiol. 2017;54:3492–505.

    Article  CAS  PubMed  Google Scholar 

  60. Wang C, He C, Lu S, Wang X, Wang L, Liang S, et al. Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF. Cell Death Dis. 2020;11:630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Natural and Science Foundation of China (81772669, 81972346 and 82173027), Scientific Research Foundation of Jilin province (20230508060RC, 20200201466JC), and Collaboration Fund of the First Hospital of Jilin University and Changchun institute of applied chemistry Chinese academy of sciences (2022YYGFZJC011).

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Authors and Affiliations

  1. Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China

    Shi-peng Liang, Xuan-zhong Wang, Xi Chen, Zhen-chuan Wang, Chen Li, Yu-bo Wang, Shan Lu, Chuan He & Peng-fei Ge

  2. Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China

    Shi-peng Liang, Xuan-zhong Wang, Xi Chen, Zhen-chuan Wang, Chen Li, Yan-li Wang & Peng-fei Ge

  3. Department of Anesthesiology, First Hospital of Jilin University, Changchun, 130021, China

    Mei-hua Piao

  4. Department of Obstetrics and Gynecology, First Hospital of Jilin University, Changchun, 130021, China

    Yan-li Wang

  5. Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China

    Guang-fan Chi

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  1. Shi-peng Liang
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Contributions

This study was conceived, designed, and interpreted by PFG, SPL, and GFC. SPL, XZW, XC, ZCW, CL, SL, CH, YBW, YLW, and MHP undertook the data acquisition and analysis. MHP and GFC were responsible for the comprehensive technical support. PFG and SPL were major contributors in writing the manuscript. MHP and GFC contributed to the inspection of data and final manuscript. All authors read and approved the final manuscript.

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Correspondence to Peng-fei Ge.

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Liang, Sp., Wang, Xz., Piao, Mh. et al. Activated SIRT1 contributes to DPT-induced glioma cell parthanatos by upregulation of NOX2 and NAT10. Acta Pharmacol Sin 44, 2125–2138 (2023). https://doi.org/10.1038/s41401-023-01109-3

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