%0 Journal Article
%T PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex.
%A Qiu L
%A Li R
%A Wang Y
%A Lu Z
%A Tu Z
%A Liu H
%J Br J Cancer
%V 131
%N 3
%D 2024 Aug 12
%M 38866962
%F 9.075
%R 10.1038/s41416-024-02749-w
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.