Exploring the Control of PARP1 Levels in High-Grade Serous Ovarian Cancer

SIMPLE SUMMARY: In high-grade serous ovarian cancer (HGSOC), the PARP (poly(ADP-ribose) polymerase) inhibitor resistance limits the therapeutic strategies. Understanding the regulation of PARP1 expression in HGSOC may be functional to overcome this issue. We recently demonstrated that, in cervical cancer cells, STAT1 (Signal Transducer and Activator of Transcription) controls PARP1 levels, also interacting with STAT3. Hence, we evaluated the possibility that the same mechanism may occur in HGSOC. The STAT1/STAT3 effects on PARP1 were studied in both established and primary HGSOC cells. Results suggest that STAT1 might act at both transcriptional and post-transcriptional levels to modulate PARP1 levels. Remarkably, bioinformatics analysis of databases revealed that higher levels of STAT1 correlate with positive outcomes, as well as with good responses to chemotherapy in HGSOC patients. These results indicate that new molecular interactions have to be studied in order to solve the PARP inhibitor resistance and to improve personalized therapeutic approaches in HGSOC. ABSTRACT: High-grade serous ovarian cancer (HGSOC) is a leading cause of mortality from gynecologic malignancies worldwide. Although a transformative improvement has been shown with the introduction of PARP (poly(ADP-ribose) polymerase) inhibitors, the emergence of resistance to these drugs represents a therapeutic challenge. Hence, expanding our understanding of mechanisms behind the control of PARP1 expression can provide strategic guidance for the translation of novel therapeutic strategies. The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors critically involved in the regulation of important cellular functions. Notably, we recently demonstrated that, in cervical cancer cells, STAT1 controls PARP1 levels through multiple mechanisms, possibly involving also STAT3. Here, we tested the hypothesis that a similar mechanism might be operative in HGSOC. To this end, the impact of STAT1/STAT3 modulation on PARP1 expression was assessed in established and primary HGSOC cells, and molecular biology studies proved that STAT1 might act at both transcriptional and post-transcriptional levels to modulate the PARP1 level. Notably, bioinformatics analysis of TCGA databases demonstrated that increased STAT1 mRNA expression levels are associated with a favorable prognosis and with response to chemotherapy in HGSOC patients. Our findings suggest an alternative strategy for targeting HGSOC cells based on their dependency on PARP1.