Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Translational Therapeutics

PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex

Abstract

Background

Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application.

Methods

Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo.

Results

In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth.

Conclusions

Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Combination of PTENi VO-OHpic with PARPi olaparib synergistically inhibited proliferation of ovarian cancer cells.
Fig. 2: VO-OHpic treatment caused DSB accumulation in ovarian cancer cells.
Fig. 3: VO-OHpic treatment reduced the MRN complex in ovarian cancer cells.
Fig. 4: Accumulation of DSB was accompanied with reduction of MRN complex and expression of MRN complex probably via decreasing PTEN/E2F1-mediated transcription with VO-OHpic treatment.
Fig. 5: PTEN knockdown increased olaparib sensitivities, inhibited the expression of MRN complex, and increased DSBs via decreasing PTEN/E2F1-mediated transcription in ovarian cancer cells.
Fig. 6: Combination of VO-OHpic with olaparib exerted enhanced inhibitory effects on tumour growth of ES2 cells in vivo.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Zhang H, Lu B. microRNAs as biomarkers of ovarian cancer. Expert Rev Anticancer Ther. 2020;20:373–85.

    Article  CAS  PubMed  Google Scholar 

  2. Dion L, Carton I, Jaillard S, Nyangoh Timoh K, Henno S, Sardain H, et al. The landscape and therapeutic implications of molecular profiles in epithelial ovarian cancer. J Clin Med. 2020;9:2239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu L, Liu P, Liang Z, Li R, Shen M, Xu H, et al. Poly (ADP-ribose) polymerase inhibitors combined with other small-molecular compounds for the treatment of ovarian cancer. Anticancer Drugs. 2019;30:554–61.

    Article  CAS  PubMed  Google Scholar 

  4. Lee A. Fuzuloparib: first approval. Drugs. 2021;81:1221–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yamashita T. [Treatment of delusions of parasitosis: efficacy of transcutaneous electrical stimulation]. Seishin Shinkeigaku Zasshi. 1986;88:1–13.

    CAS  PubMed  Google Scholar 

  6. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–7.

    Article  CAS  PubMed  Google Scholar 

  7. Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12:852–61.

    Article  CAS  PubMed  Google Scholar 

  8. Bitler BG, Watson ZL, Wheeler LJ, Behbakht K. PARP inhibitors: clinical utility and possibilities of overcoming resistance. Gynecol Oncol. 2017;147:695–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chow JT, Salmena L. Recent advances in PTEN signalling axes in cancer. Fac Rev. 2020;9:31.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128:157–70.

    Article  CAS  PubMed  Google Scholar 

  11. Planchon SM, Waite KA, Eng C. The nuclear affairs of PTEN. J Cell Sci. 2008;121:249–53.

    Article  CAS  PubMed  Google Scholar 

  12. Ming M, He YY. PTEN in DNA damage repair. Cancer Lett. 2012;319:125–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McEllin B, Camacho CV, Mukherjee B, Hahm B, Tomimatsu N, Bachoo RM, et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 2010;70:5457–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dedes KJ, Wetterskog D, Mendes-Pereira AM, Natrajan R, Lambros MB, Geyer FC, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Transl Med. 2010;2:53ra75.

    Article  PubMed  Google Scholar 

  16. Hopkins BD, Hodakoski C, Barrows D, Mense SM, Parsons RE. PTEN function: the long and the short of it. Trends Biochem Sci. 2014;39:183–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998;280:1614–7.

    Article  CAS  PubMed  Google Scholar 

  18. Liu H, Lu Z, Shi X, Liu L, Zhang P, Golemis EA, et al. HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression. J Biol Chem. 2021;297:100996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao Z, Shang D, Qiu L, Guo C, Li Y, Liu H, et al. 4,5-Diphenyl-2-methyl picolinate induces cellular senescence by accumulating DNA damage and activating associated signaling pathways in gastric cancer. Life Sci. 2019;238:116973.

    Article  CAS  PubMed  Google Scholar 

  20. Chen S, Gu T, Lu Z, Qiu L, Xiao G, Zhu X, et al. Roles of MYC-targeting long non-coding RNA MINCR in cell cycle regulation and apoptosis in non-small cell lung Cancer. Respir Res. 2019;20:202.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shang DS, Zhou TC, Zhuang XY, Wu YF, Liu HQ, Tu ZG. Molecular dissection on inhibition of Ras-induced cellular senescence by small t antigen of SV40. Cell Mol Life Sci. 2022;79:242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lanczky A, Gyorffy B. Web-based survival analysis tool tailored for medical research (KMplot): development and implementation. J Med Internet Res. 2021;23:e27633.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19:649–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tu Z, Aird KM, Bitler BG, Nicodemus JP, Beeharry N, Xia B, et al. Oncogenic Ras regulates BRIP1 expression to induce dissociation of BRCA1 from chromatin, inhibit DNA repair, and promote senescence. Dev Cell. 2011;21:1077–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu Z, Yuan S, Ruan L, Tu Z, Liu H. Partitioning defective 6 homolog alpha (PARD6A) promotes epithelial-mesenchymal transition via integrin β1-ILK-SNAIL1 pathway in ovarian cancer. Cell Death Dis. 2022;13:304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ledermann JA, Drew Y, Kristeleit RS. Homologous recombination deficiency and ovarian cancer. Eur J Cancer. 2016;60:49–58.

    Article  CAS  PubMed  Google Scholar 

  28. Boussios S, Karihtala P, Moschetta M, Karathanasi A, Sadauskaite A, Rassy E, et al. Combined strategies with poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer: a literature review. Diagnostics. 2019;9:87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Arora S, Balasubramaniam S, Zhang H, Berman T, Narayan P, Suzman D, et al. FDA approval summary: olaparib monotherapy or in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer. Oncologist. 2021;26:e164–72.

    Article  CAS  PubMed  Google Scholar 

  30. Alfieri R, Giovannetti E, Bonelli M, Cavazzoni A. New treatment opportunities in phosphatase and tensin homolog (PTEN)-deficient tumors: focus on PTEN/focal adhesion kinase pathway. Front Oncol. 2017;7:170.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19:547–62.

    Article  CAS  PubMed  Google Scholar 

  32. Li S, Zhu M, Pan R, Fang T, Cao YY, Chen S, et al. The tumor suppressor PTEN has a critical role in antiviral innate immunity. Nat Immunol. 2016;17:241–9.

    Article  CAS  PubMed  Google Scholar 

  33. Bian L, Meng Y, Zhang M, Li D. MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment. Mol Cancer. 2019;18:169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Elkholi IE, Foulkes WD, Rivera B. MRN complex and cancer risk: old bottles, new wine. Clin Cancer Res. 2021;27:5465–71.

    Article  CAS  PubMed  Google Scholar 

  35. Syed A, Tainer JA. The MRE11-RAD50-NBS1 complex conducts the orchestration of damage signaling and outcomes to stress in DNA replication and repair. Annu Rev Biochem. 2018;87:263–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yuan J, Song Y, Pan W, Li Y, Xu Y, Xie M, et al. LncRNA SLC26A4-AS1 suppresses the MRN complex-mediated DNA repair signaling and thyroid cancer metastasis by destabilizing DDX5. Oncogene. 2020;39:6664–76.

    Article  CAS  PubMed  Google Scholar 

  37. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.

    Article  CAS  PubMed  Google Scholar 

  38. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356–62.

    Article  CAS  PubMed  Google Scholar 

  39. Rosivatz E, Matthews JG, McDonald NQ, Mulet X, Ho KK, Lossi N, et al. A small-molecule inhibitor for phosphatase and tensin homologue deleted on chromosome 10 (PTEN). ACS Chem Biol. 2006;1:780–90.

    Article  CAS  PubMed  Google Scholar 

  40. Bassi C, Ho J, Srikumar T, Dowling RJ, Gorrini C, Miller SJ, et al. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science. 2013;341:395–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ho J, Cruise ES, Dowling RJO, Stambolic V. PTEN nuclear functions. Cold Spring Harb Perspect Med. 2020;10:a036079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shi LG, Li BC, Zhang BN, Zhen CY, Zhou JD, Tang SJ. Mouse embryonic palatal mesenchymal cells maintain stemness through the PTEN-Akt-mTOR autophagic pathway. Stem Cell Res Ther. 2019;10:217.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kim SJ, Lee HW, Baek JH, Cho YH, Kang HG, Jeong JS, et al. Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer. Oncogene. 2016;35:251–60.

    Article  CAS  PubMed  Google Scholar 

  44. Wu Y, Zhou H, Wu K, Lee S, Li RJ, Liu X. PTEN phosphorylation and nuclear export mediate free fatty acid-induced oxidative stress. Antioxid Redox Signal. 2014;20:1382–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN tumor suppression. Cell. 2008;133:403–14.

    Article  CAS  PubMed  Google Scholar 

  46. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.

    Article  PubMed Central  Google Scholar 

  47. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014;20:764–75.

    Article  CAS  PubMed  Google Scholar 

  48. Brandt S, Samartzis EP, Zimmermann AK, Fink D, Moch H, Noske A, et al. Lack of MRE11-RAD50-NBS1 (MRN) complex detection occurs frequently in low-grade epithelial ovarian cancer. BMC Cancer. 2017;17:44.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Koppensteiner R, Samartzis EP, Noske A, von Teichman A, Dedes I, Gwerder M, et al. Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PLoS ONE. 2014;9:e100041.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Lu HM, Li S, Black MH, Lee S, Hoiness R, Wu S, et al. Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol. 2019;5:51–7.

    Article  PubMed  Google Scholar 

  51. Lajud SA, Nagda DA, Yamashita T, Zheng J, Tanaka N, Abuzeid WM, et al. Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer. Clin Cancer Res. 2014;20:6465–78.

    Article  CAS  PubMed  Google Scholar 

  52. Oplustilova L, Wolanin K, Mistrik M, Korinkova G, Simkova D, Bouchal J, et al. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment. Cell Cycle. 2012;11:3837–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. De Lorenzo SB, Patel AG, Hurley RM, Kaufmann SH. The elephant and the blind men: making sense of PARP inhibitors in homologous recombination deficient tumor cells. Front Oncol. 2013;3:228.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Miller RE, El-Shakankery KH, Lee JY. PARP inhibitors in ovarian cancer: overcoming resistance with combination strategies. J Gynecol Oncol. 2022;33:e44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shibata A, Moiani D, Arvai AS, Perry J, Harding SM, Genois MM, et al. DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol Cell. 2014;53:7–18.

    Article  CAS  PubMed  Google Scholar 

  56. Yang YG, Saidi A, Frappart PO, Min W, Barrucand C, Dumon-Jones V, et al. Conditional deletion of Nbs1 in murine cells reveals its role in branching repair pathways of DNA double-strand breaks. EMBO J. 2006;25:5527–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Karakashev S, Fukumoto T, Zhao B, Lin J, Wu S, Fatkhutdinov N, et al. EZH2 inhibition sensitizes CARM1-high, homologous recombination proficient ovarian cancers to PARP inhibition. Cancer Cell. 2020;37:157–67.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Piscitello D, Varshney D, Lilla S, Vizioli MG, Reid C, Gorbunova V, et al. AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11. Oncogene. 2018;37:427–38.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China [Grant number 81672582 (to HL) and 31771521 (to ZT)]; Top Talent of Innovative Research Team of Jiangsu Province (to HL and ZT); the Natural Science Foundation of Jiangsu Province [Grant number BE2016718 (to ZT)]; the Training Project for Young Backbone Teachers of Jiangsu University (to LQ).

Author information

Authors and Affiliations

Authors

Contributions

Experimental design and supervision: ZT and HL; Data analysis and interpretation: LQ, RL, and YW; Bioinformatic correlation analysis: LQ; In vitro assays: RL, YW, and LQ; In vivo experiments: ZL; Paper writing: LQ, ZT, and HL.

Corresponding authors

Correspondence to Zhigang Tu or Hanqing Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The animal study was reviewed and approved by Bioethics Committee of Jiangsu University. All methods were performed in accordance with the relevant guidelines and regulations.

Additional information

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

Supplementary information

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

Qiu, L., Li, R., Wang, Y. et al. PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02749-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41416-024-02749-w

Search

Quick links