Skip to main content

Advertisement

SpringerLink
Log in

Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer

  • Research
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research.

Methods

The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments.

Results

We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission.

Conclusion

Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, Global Cancer Statistics 2020, GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71, 209–249 (2021)

    Article  PubMed  Google Scholar 

  2. R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal, Cancer statistics, 2022. CA Cancer J Clin. 72, 7–33 (2022)

    Article  PubMed  Google Scholar 

  3. C. Tran, S. Ouk, N.J. Clegg, Y. Chen, P.A. Watson, V. Arora, J. Wongvipat, P.M. Smith-Jones, D. Yoo, A. Kwon, T. Wasielewska, D. Welsbie, C.D. Chen, C.S. Higano, T.M. Beer, D.T. Hung, H.I. Scher, M.E. Jung, C.L. Sawyers, Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 324, 787–790 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. A.H. Davies, H. Beltran, A. Zoubeidi, Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat. Rev. Urol. 15, 271–286 (2018)

    Article  CAS  PubMed  Google Scholar 

  5. D. Robinson, E.M. Van Allen, Y.M. Wu, N. Schultz, R.J. Lonigro, J.M. Mosquera, B. Montgomery, M.E. Taplin, C.C. Pritchard, G. Attard, H. Beltran, W. Abida, R.K. Bradley, J. Vinson, X.H. Cao, P. Vats, L.P. Kunju, M. Hussain, F.Y. Feng, S.A. Tomlins, K.A. Cooney, D.C. Smith, C. Brennan, J. Siddiqui, R. Mehra, Y. Chen, D.E. Rathkopf, M.J. Morris, S.B. Solomon, J.C. Durack, V.E. Reuter, A. Gopalan, J.J. Gao, M. Loda, R.T. Lis, M. Bowden, S.P. Balk, G. Gaviola, C. Sougnez, M. Gupta, E.Y. Yu, E.A. Mostaghel, H.H. Cheng, H. Mulcahy, L.D. True, S.R. Plymate, H. Dvinge, R. Ferraldeschi, P. Flohr, S. Miranda, Z. Zafeiriou, N. Tunariu, J. Mateo, R. Perez-Lopez, F. Demichelis, B.D. Robinson, M. Schiffman, D.M. Nanus, S.T. Tagawa, A. Sigaras, K.W. Eng, O. Elemento, A. Sboner, E.I. Heath, H.I. Scher, K.J. Pienta, P. Kantoff, J.S. de Bono, M.A., P.S. Rubin, Nelson, L.A., Garraway, C.L. Sawyers and A.M. Chinnaiyan, Integrative Clinical Genomics of Advanced Prostate Cancer. Cell. 161, 1215–1228 (2015)

  6. J. Mateo, S. Carreira, S. Sandhu, S. Miranda, H. Mossop, R. Perez-Lopez, D. Nava Rodrigues, D. Robinson, A. Omlin, N. Tunariu, G. Boysen, N. Porta, P. Flohr, A. Gillman, I. Figueiredo, C. Paulding, G. Seed, S. Jain, C. Ralph, A. Protheroe, S. Hussain, R. Jones, T. Elliott, U. McGovern, D. Bianchini, J. Goodall, Z. Zafeiriou, C.T. Williamson, R. Ferraldeschi, R. Riisnaes, B. Ebbs, G. Fowler, D. Roda, W. Yuan, Y.M. Wu, X. Cao, R. Brough, H. Pemberton, R. A’Hern, A. Swain, L.P. Kunju, R. Eeles, G. Attard, C.J. Lord, A. Ashworth, M.A. Rubin, K.E. Knudsen, F.Y. Feng, A.M. Chinnaiyan, Hall and J.S. de Bono, DNA-Repair defects and Olaparib in metastatic prostate Cancer. N Engl. J. Med. 373, 1697–1708 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. J. de Bono, J. Mateo, K. Fizazi, F. Saad, N. Shore, S. Sandhu, K.N. Chi, O. Sartor, N. Agarwal, D. Olmos, A. Thiery-Vuillemin, P. Twardowski, N. Mehra, C. Goessl, J. Kang, J. Burgents, W. Wu, A. Kohlmann, C.A. Adelman, M. Hussain, Olaparib for metastatic castration-resistant prostate Cancer. N Engl. J. Med. 382, 2091–2102 (2020)

    Article  PubMed  Google Scholar 

  8. M. Hussain, J. Mateo, K. Fizazi, F. Saad, N. Shore, S. Sandhu, K.N. Chi, O. Sartor, N. Agarwal, D. Olmos, A. Thiery-Vuillemin, P. Twardowski, G. Roubaud, M. Ozguroglu, J. Kang, J. Burgents, C. Gresty, C. Corcoran, C.A. de Adelman, Bono and P.R.T. investigators, survival with Olaparib in Metastatic Castration-Resistant prostate Cancer. N Engl. J. Med. 383, 2345–2357 (2020)

    Article  CAS  PubMed  Google Scholar 

  9. M.P. Dias, S.C. Moser, S. Ganesan, J. Jonkers, Understanding and overcoming resistance to PARP inhibitors in cancer therapy. Nat. Rev. Clin. Oncol. 18, 773–791 (2021)

    Article  PubMed  Google Scholar 

  10. G. van Camp, P. Coucke, W. Balemans, D. van Velzen, C. van de Bilt, L. van Laer, R.J. Smith, K. Fukushima, G.W. Padberg, R.R. Frants, Localization of a gene for non-syndromic hearing loss (DFNA5) to chromosome 7p15. Hum. Mol. Genet. 4, 2159–2163 (1995)

    Article  PubMed  Google Scholar 

  11. L. Galluzzi, I. Vitale, S.A. Aaronson, J.M. Abrams, D. Adam, P. Agostinis, E.S. Alnemri, L. Altucci, I. Amelio, D.W. Andrews, M. Annicchiarico-Petruzzelli, A.V. Antonov, E. Arama, E.H. Baehrecke, N.A. Barlev, N.G. Bazan, F. Bernassola, M.J.M. Bertrand, K. Bianchi, M.V. Blagosklonny, K. Blomgren, C. Borner, P. Boya, C. Brenner, M. Campanella, E. Candi, D. Carmona-Gutierrez, F. Cecconi, F.K. Chan, N.S. Chandel, E.H. Cheng, J.E. Chipuk, J.A. Cidlowski, A. Ciechanover, G.M. Cohen, M. Conrad, J.R. Cubillos-Ruiz, P.E. Czabotar, V. D'Angiolella, T.M. Dawson, V.L. Dawson, V. De Laurenzi, R. De Maria, K.M. Debatin, R.J. DeBerardinis, M. Deshmukh, N. Di Daniele, F. Di Virgilio, V.M. Dixit, S.J. Dixon, C.S. Duckett, B.D. Dynlacht, W.S. El-Deiry, J.W. Elrod, G.M. Fimia, S. Fulda, A.J. Garcia-Saez, A.D. Garg, C. Garrido, E. Gavathiotis, P. Golstein, E. Gottlieb, D.R. Green, L.A. Greene, H. Gronemeyer, A. Gross, G. Hajnoczky, J.M. Hardwick, I.S. Harris, M.O. Hengartner, C. Hetz, H. Ichijo, M. Jaattela, B. Joseph, P.J. Jost, P.P. Juin, W.J. Kaiser, M. Karin, T. Kaufmann, O. Kepp, A. Kimchi, R.N. Kitsis, D.J. Klionsky, R.A. Knight, S. Kumar, S.W. Lee, J.J. Lemasters, B. Levine, A. Linkermann, S.A. Lipton, R.A. Lockshin, C. Lopez-Otin, S.W. Lowe, T. Luedde, E. Lugli, M. MacFarlane, F. Madeo, M. Malewicz, W. Malorni, G. Manic, J.C. Marine, S.J. Martin, J.C. Martinou, J.P. Medema, P. Mehlen, P. Meier, S. Melino, E.A. Miao, J.D. Molkentin, U.M. Moll, C. Munoz-Pinedo, S. Nagata, G. Nunez, A. Oberst, M. Oren, M. Overholtzer, M. Pagano, T. Panaretakis, M. Pasparakis, J.M. Penninger, D.M. Pereira, S. Pervaiz, M.E. Peter, M. Piacentini, P. Pinton, J.H.M. Prehn, H. Puthalakath, G.A. Rabinovich, M. Rehm, R. Rizzuto, C.M.P. Rodrigues, D.C. Rubinsztein, T. Rudel, K.M. Ryan, E. Sayan, L. Scorrano, F. Shao, Y. Shi, J. Silke, H.U. Simon, A. Sistigu, B.R. Stockwell, A. Strasser, G. Szabadkai, S.W.G. Tait, D. Tang, N. Tavernarakis, A. Thorburn, Y. Tsujimoto, B. Turk, T. Vanden Berghe, P. Vandenabeele, M.G. Vander Heiden, A. Villunger, H.W. Virgin, K.H. Vousden, D. Vucic, E.F. Wagner, H. Walczak, D. Wallach, Y. Wang, J.A. Wells, W. Wood, J. Yuan, Z. Zakeri, B. Zhivotovsky, L. Zitvogel, G. Melino and G. Kroemer, Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018)

  12. Z. Zhang, Y. Zhang, S. Xia, Q. Kong, S. Li, X. Liu, C. Junqueira, K.F. Meza-Sosa, T.M.Y. Mok, J. Ansara, S. Sengupta, Y. Yao, H. Wu, J. Lieberman, Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 579, 415–420 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Y.P. Wang, W.Q. Gao, X.Y. Shi, J.J. Ding, W. Liu, H.B. He, K. Wang, F. Shao, Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 547, 99–103 (2017)

    Article  CAS  PubMed  Google Scholar 

  14. J. Ibrahim, K.O. de Beeck, E. Fransen, L. Croes, M. Beyens, A. Suls, W. Vanden Berghe, M. Peeters, G. Van Camp, Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer. Cancer Med-Us. 8, 2133–2145 (2019)

    Article  CAS  Google Scholar 

  15. M.S. Kim, X. Chang, K. Yamashita, J.K. Nagpal, J.H. Baek, G. Wu, B. Trink, E.A. Ratovitski, M. Mori, D. Sidransky, Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma. Oncogene. 27, 3624–3634 (2008)

    Article  CAS  PubMed  Google Scholar 

  16. K. Akino, M. Toyota, H. Suzuki, T. Imai, R. Maruyama, M. Kusano, N. Nishikawa, Y. Watanabe, Y. Sasaki, T. Abe, E. Yamamoto, I. Tarasawa, T. Sonoda, M. Mori, K. Imai, Y. Shinomura, T. Tokino, Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer. Cancer Sci. 98, 88–95 (2007)

    Article  CAS  PubMed  Google Scholar 

  17. M. Katoh, M. Katoh, Identification and characterization of human DFNA5L, mouse Dfna5l, and rat Dfna5l genes in silico. Int. J. Oncol. 25, 765–770 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Y. Zhang, J. Yang, Z. Wen, X. Chen, J. Yu, D. Yuan, B. Xu, H. Luo, J. Zhu, A novel 3’,5’-diprenylated chalcone induces concurrent apoptosis and GSDME-dependent pyroptosis through activating PKCdelta/JNK signal in prostate cancer. Aging (Albany NY). 12, 9103–9124 (2020)

    Article  CAS  PubMed  Google Scholar 

  19. C.J. Wang, L. Tang, D.W. Shen, C. Wang, Q.Y. Yuan, W. Gao, Y.K. Wang, R.H. Xu, H. Zhang, The expression and regulation of DFNA5 in human hepatocellular carcinoma DFNA5 in hepatocellular carcinoma. Mol. Biol. Rep. 40, 6525–6531 (2013)

    Article  CAS  PubMed  Google Scholar 

  20. J. Yu, B. Qin, A.M. Moyer, S. Nowsheen, T. Liu, S. Qin, Y. Zhuang, D. Liu, S.W. Lu, K.R. Kalari, D.W. Visscher, J.A. Copland, S.A. McLaughlin, A. Moreno-Aspitia, D.W. Northfelt, R.J. Gray, Z. Lou, V.J. Suman, R. Weinshilboum, J.C. Boughey, M.P. Goetz, L. Wang, DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine. J. Clin. Invest. 128, 2376–2388 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  21. E. Kaminskas, A. Farrell, S. Abraham, A. Baird, L.S. Hsieh, S.L. Lee, J.K. Leighton, H. Patel, A. Rahman, R. Sridhara, Y.C. Wang, Pazdur and Fda, approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin. Cancer Res. 11, 3604–3608 (2005)

    Article  CAS  PubMed  Google Scholar 

  22. C. Rogers, T. Fernandes-Alnemri, L. Mayes, D. Alnemri, G. Cingolani, E.S. Alnemri, Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8, 14128 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. A. Subramanian, P. Tamayo, V.K. Mootha, S. Mukherjee, B.L. Ebert, M.A. Gillette, A. Paulovich, S.L. Pomeroy, T.R. Golub, E.S. Lander, J.P. Mesirov, Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. U S A 102, 15545–15550 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. V.K. Mootha, C.M. Lindgren, K.F. Eriksson, A. Subramanian, S. Sihag, J. Lehar, P. Puigserver, E. Carlsson, M. Ridderstrale, E. Laurila, N. Houstis, M.J. Daly, N. Patterson, J.P. Mesirov, T.R. Golub, P. Tamayo, B. Spiegelman, E.S. Lander, J.N. Hirschhorn, D. Altshuler, L.C. Groop, PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003)

    Article  CAS  PubMed  Google Scholar 

  25. W. Ding, G. Feng, Y. Hu, G. Chen, T. Shi, Co-occurrence and mutual exclusivity analysis of DNA methylation reveals distinct subtypes in multiple cancers. Front. Cell. Dev. Biol. 8, 20 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  26. Z. Xiong, F. Yang, M. Li, Y. Ma, W. Zhao, G. Wang, Z. Li, X. Zheng, D. Zou, W. Zong, H. Kang, Y. Jia, R. Li, Z. Zhang, Y. Bao, EWAS Open platform: integrated data, knowledge and toolkit for epigenome-wide association study. Nucleic Acids Res. 50, D1004–D1009 (2022)

    Article  CAS  PubMed  Google Scholar 

  27. L. Croes, M. Beyens, E. Fransen, J. Ibrahim, W.V. Berghe, A. Suls, M. Peeters, P. Pauwels, G. Van Camp, K.O. de Beeck, Large-scale analysis of DFNA5 methylation reveals its potential as biomarker for breast cancer. Clin. Epigenetics. 10, 51 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  28. J. Hu, F.J. Sanchez-Rivera, Z. Wang, G.N. Johnson, Y.J. Ho, K. Ganesh, S. Umeda, S. Gan, A.M. Mujal, R.B. Delconte, J.P. Hampton, H. Zhao, S. Kottapalli, E. de Stanchina, C.A. Iacobuzio-Donahue, D. Pe’er, S.W. Lowe, J.C. Sun, J. Massague, STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature. 616, 806–813 (2023)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. D.A. Moser, S. Muller, E.M. Hummel, A.S. Limberg, L. Dieckmann, L. Frach, J. Pakusch, V. Flasbeck, M. Brune, J. Beygo, L. Klein-Hitpass, R. Kumsta, Targeted bisulfite sequencing: a novel tool for the assessment of DNA methylation with high sensitivity and increased coverage. Psychoneuroendocrinology. 120, 104784 (2020)

    Article  CAS  PubMed  Google Scholar 

  30. Y. Zhang, T. Wu, Y. Wang, Z. Chen, J. Chen, S. Lu, W. Xia, Reciprocal FGF19-GLI2 signaling induces epithelial-to-mesenchymal transition to promote lung squamous cell carcinoma metastasis. Cell. Oncol. 46, 437–450 (2023)

    Article  CAS  Google Scholar 

  31. Y. Zhang, T. Wu, F. Li, Y. Cheng, Q. Han, X. Lu, S. Lu, W. Xia, FGF19 is Coamplified with CCND1 to promote proliferation in lung squamous cell carcinoma and their combined inhibition shows improved efficacy. Front. Oncol. 12, 846744 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Q. Han, Q.R. Xie, F. Li, Y. Cheng, T. Wu, Y. Zhang, X. Lu, A.S.T. Wong, J. Sha, W. Xia, Targeted inhibition of SIRT6 via engineered exosomes impairs tumorigenesis and metastasis in prostate cancer. Theranostics. 11, 6526–6541 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. W. Gong, P. Fang, M. Leng, Y. Shi, Promoting GSDME expression through DNA demethylation to increase chemosensitivity of breast cancer MCF-7 / taxol cells. Plos One 18, e0282244 (2023)

  34. X. Wei, F. Xie, X. Zhou, Y. Wu, H. Yan, T. Liu, J. Huang, F. Wang, F. Zhou, L. Zhang, Role of pyroptosis in inflammation and cancer. Cell. Mol. Immunol. 19, 971–992 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. J. Armenia, S.A.M. Wankowicz, D. Liu, J. Gao, R. Kundra, E. Reznik, W.K. Chatila, D. Chakravarty, G.C. Han, I. Coleman, B. Montgomery, C. Pritchard, C. Morrissey, C.E. Barbieri, H. Beltran, A. Sboner, Z. Zafeiriou, S. Miranda, C.M. Bielski, A.V. Penson, C. Tolonen, F.W. Huang, D. Robinson, Y.M. Wu, R. Lonigro, L.A. Garraway, F. Demichelis, P.W. Kantoff, M.E. Taplin, W. Abida, B.S. Taylor, H.I. Scher, P.S. Nelson, J.S. de Bono, M.A. Rubin, C.L. Sawyers, A.M. Chinnaiyan, P.S.C.I.P.C.D. Team, N. Schultz and E.M. Van Allen, the long tail of oncogenic drivers in prostate cancer. Nat. Genet. 50, 645–651 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. P.A. Jones, S.M. Taylor, Cellular differentiation, cytidine analogs and DNA methylation. Cell. 20, 85–93 (1980)

    Article  CAS  PubMed  Google Scholar 

  37. K. Yokomizo, Y. Harada, K. Kijima, K. Shinmura, M. Sakata, K. Sakuraba, Y. Kitamura, A. Shirahata, T. Goto, H. Mizukami, M. Saito, G. Kigawa, H. Nemoto, K. Hibi, Methylation of the DFNA5 gene is frequently detected in Colorectal Cancer. Anticancer Res. 32, 1319–1322 (2012)

    CAS  PubMed  Google Scholar 

  38. J. Lv, Y. Liu, S. Mo, Y. Zhou, F. Chen, F. Cheng, C. Li, D. Saimi, M. Liu, H. Zhang, K. Tang, J. Ma, Z. Wang, Q. Zhu, W.M. Tong, B. Huang, Gasdermin E mediates resistance of pancreatic adenocarcinoma to enzymatic digestion through a YBX1-mucin pathway. Nat. Cell. Biol. 24, 364–372 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Y. Ren, M. Feng, X. Liu, X. Hao, J. Li, P. Li, J. Gao, Q. Qi, L. Du, C. Wang, Q. Wang, Y. Wang, USP48 stabilizes gasdermin E to promote pyroptosis in cancer. Cancer Res. 83, 1074–1093 (2023)

    Article  CAS  PubMed  Google Scholar 

  40. N.J. Curtin, C. Szabo, Poly(ADP-ribose) polymerase inhibition: past, present and future. Nat. Rev. Drug Discov. 19, 711–736 (2020)

    Article  CAS  PubMed  Google Scholar 

  41. C.J. Lord, A. Ashworth, PARP inhibitors: synthetic lethality in the clinic. Science. 355, 1152–1158 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. C. Kim, X.D. Wang, Y. Yu, PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response. Elife 9, e60637 (2020)

  43. A.P. Lombard, C.M. Armstrong, L.S. D’Abronzo, S. Ning, A.R. Leslie, M. Sharifi, W. Lou, C.P. Evans, M. Dall’Era, H.W. Chen, X. Chen, A.C. Gao, Olaparib-Induced Senescence is bypassed through G2-M checkpoint override in Olaparib-Resistant prostate Cancer. Mol. Cancer Ther. 21, 677–685 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. C. Kim, X.D. Wang, S. Jang, Y. Yu, PARP1 inhibitors induce pyroptosis via caspase 3-mediated gasdermin E cleavage. Biochem. Biophys. Res. Commun. 646, 78–85 (2023)

    Article  CAS  PubMed  Google Scholar 

  45. J. Shen, W. Zhao, Z. Ju, L. Wang, Y. Peng, M. Labrie, T.A. Yap, G.B. Mills, G. Peng, PARPi triggers the STING-Dependent Immune response and enhances the therapeutic efficacy of Immune Checkpoint Blockade Independent of BRCAness. Cancer Res. 79, 311–319 (2019)

    Article  CAS  PubMed  Google Scholar 

  46. A. Kumaraswamy, K.R. Welker Leng, T.C. Westbrook, J.A. Yates, S.G. Zhao, C.P. Evans, F.Y. Feng, T.M. Morgan, J.J. Alumkal, Recent advances in epigenetic biomarkers and epigenetic targeting in prostate Cancer. Eur. Urol. 80, 71–81 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. S.G. Zhao, W.S. Chen, H. Li, A. Foye, M. Zhang, M. Sjostrom, R. Aggarwal, D. Playdle, A. Liao, J.J. Alumkal, R. Das, J. Chou, J.T. Hua, T.J. Barnard, A.M. Bailey, E.D. Chow, M.D. Perry, H.X. Dang, R. Yang, R. Moussavi-Baygi, L. Zhang, M. Alshalalfa, S. Laura Chang, K.E. Houlahan, Y.J. Shiah, T.M. Beer, G. Thomas, K.N. Chi, M. Gleave, A. Zoubeidi, R.E. Reiter, M.B. Rettig, O. Witte, M. Yvonne Kim, L. Fong, D.E. Spratt, T.M. Morgan, R. Bose, F.W. Huang, H. Li, L. Chesner, T. Shenoy, H. Goodarzi, I.A. Asangani, S. Sandhu, J.M. Lang, N.P. Mahajan, P.N. Lara, C.P. Evans, P. Febbo, S. Batzoglou, K.E. Knudsen, H.H. He, J. Huang, W. Zwart, J.F. Costello, J. Luo, S.A. Tomlins, A.W. Wyatt, S.M. Dehm, A. Ashworth, L.A. Gilbert, P.C. Boutros, K. Farh, A.M. Chinnaiyan, C.A. Maher, E.J. Small, D.A. Quigley and F.Y. Feng, The DNA methylation landscape of advanced prostate cancer. Nat Genet. 52, 778–789 (2020)

  48. K.E. Houlahan, Y.J. Shiah, A. Gusev, J. Yuan, M. Ahmed, A. Shetty, S.G. Ramanand, C.Q. Yao, C. Bell, E. O’Connor, V. Huang, M. Fraser, L.E. Heisler, J. Livingstone, T.N. Yamaguchi, A. Rouette, A. Foucal, S.M.G. Espiritu, A. Sinha, M. Sam, L. Timms, J. Johns, A. Wong, A. Murison, M. Orain, V. Picard, H. Hovington, A. Bergeron, L. Lacombe, M. Lupien, Y. Fradet, B. Tetu, J.D. McPherson, B. Pasaniuc, T. Kislinger, M.L.K. Chua, M.M. Pomerantz, T. van der Kwast, M.L. Freedman, R.S. Mani, H.H. He, R.G. Bristow, P.C. Boutros, Genome-wide germline correlates of the epigenetic landscape of prostate cancer. Nat. Med. 25, 1615–1626 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. J.I. Shim, J.Y. Ryu, S.Y. Jeong, Y.J. Cho, J.J. Choi, J.R. Hwang, J.Y. Choi, J.K. Sa, J.W. Lee, Combination effect of poly (ADP-ribose) polymerase inhibitor and DNA demethylating agents for treatment of epithelial ovarian cancer. Gynecol. Oncol. 165, 270–280 (2022)

    Article  CAS  PubMed  Google Scholar 

  50. M.L. Orta, A. Höglund, J.M. Calderón-Montaño, I. Domínguez, E. Burgos-Morón, T. Visnes, N. Pastor, C. Ström, M. López-lázaro, T. Helleday, The PARP inhibitor Olaparib disrupts base excision repair of 5-aza-2’-deoxycytidine lesions. Nucleic Acids Res. 42, 9108–9120 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. B.C. Valdez, Y. Li, D. Murray, Y. Liu, Y. Nieto, R.E. Champlin, B.S. Andersson, Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells. Oncotarget. 9, 3908–3921 (2018)

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciated the free access to TCGA, GEO, DNMIVD and EWAS Data Hub databases and GSEA software.

Funding

This work was supported by grants from Ministry of Science and Technology (2022YFC2702703), Science and Technology Commission of Shanghai Municipality (21ZR1433100), and SJTU funding (YG2022ZD016).

Author information

Author notes

  1. Ao Tian and Tingyu Wu contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China

    Ao Tian, Tingyu Wu, Yanshuang Zhang, Jiachen Chen & Weiliang Xia

  2. Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shandong Middle road, Shanghai, 200001, China

    Jianjun Sha

Authors
  1. Ao Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tingyu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanshuang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiachen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianjun Sha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weiliang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.W. conceived and designed the experiments. T.W. and A.T. performed the experiments, acquired, and analyzed data, presented figures, and wrote manuscript of the paper. Y.Z. and J.C. performed the experiments and analyzed the data. J.S. provided the clinical-related materials. W.X. acquired fundings and supervised experiments. W.X. conceived and designed the experiments, reviewed drafts of the paper, and approved the final draft.

Corresponding author

Correspondence to Weiliang Xia.

Ethics declarations

Ethics approval and consent to participate

Ethics committee approval from School of Biomedical Engineering, Shanghai Jiao Tong University (Shanghai, China) was obtained prior to the research and informed written consent of all participants were obtained. All animal studies were performed following the Institutional Ethics Committee of School of Biomedical Engineering, Shanghai Jiao Tong University (Shanghai, China).

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tian, A., Wu, T., Zhang, Y. et al. Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer. Cell Oncol. 46, 1855–1870 (2023). https://doi.org/10.1007/s13402-023-00860-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-023-00860-3

Keywords

Search

Navigation