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Translational Therapeutics

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

British Journal of Cancer volume 131, pages 577–588 (2024)Cite this article

Subjects

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.

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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.

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Data availability

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

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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).

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Author notes

  1. Ruyan Li

    Present address: School of Health Medicine, Nantong Institute of Technology, Nantong, 226000, Jiangsu, China

  2. These authors contributed equally: Lipeng Qiu, Ruyan Li, Yue Wang.

Authors and Affiliations

  1. School of Life Sciences, Jiangsu University, Zhenjiang, 212013, Jiangsu, China

    Lipeng Qiu, Ruyan Li, Yue Wang, Ziwen Lu & Zhigang Tu

  2. School of Pharmacy, Jiangsu University, Zhenjiang, 212013, Jiangsu, China

    Hanqing Liu

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  1. Lipeng Qiu
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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.

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Correspondence to Zhigang Tu or Hanqing Liu.

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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.

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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 131, 577–588 (2024). https://doi.org/10.1038/s41416-024-02749-w

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