Stat1 confers sensitivity to radiation in cervical cancer cells by controlling Parp1 levels: a new perspective for Parp1 inhibition

Giuseppina Raspaglio,Flavia Filippetti,Alessandra Battaglia,Alexia Buzzonetti,Marianna Buttarelli,Giovanni Scambia,Daniela Gallo

doi:10.1038/s41419-021-04229-y

Giuseppina Raspaglio, Flavia Filippetti + Show 5 more

Open Access

https://doi.org/10.1038/s41419-021-04229-y

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Abstract

Cervical cancer (CC) is the fourth most common cause of cancer-related death in women. According to international guidelines, a standard treatment for locally advanced cervical cancer (LACC) consists of exclusive concurrent chemoradiation treatment (CRT). However, chemoradioresistance and subsequent relapse and metastasis of cancer occur in many patients, and survival for these women has generally remained poor. Therefore, strategies to overcome resistance are urgently needed. We have recently reported a radiosensitizing effect of the signal transducer and activator of transcription 1 (STAT1) in CC, associated with the control of [Poly(ADP-ribose) polymerase −1] PARP1 levels, a key factor in cell response to DNA damage induced by radiation. Here, we sought to decipher the underlying mechanism of STAT1-mediated control of PARP1, elucidating its role as a radiosensitizer in CC. Functional and molecular biology studies demonstrated that STAT1 may act at both transcriptional and posttranscriptional levels to modulate PARP1 expression in CC cells. In light of these results, we tested the effect of Olaparib in sensitizing CC cells to radiation and investigated signaling pathways involved in the activity observed. Results showed that PARP1 inhibition, at clinically achievable doses, may indeed selectively improve the sensitivity of resistant CC cells to DNA-damaging treatment. The translational relevance of our findings was supported by preliminary results in a limited patient cohort, confirming that higher PARP1 levels are significantly associated with a radioresistant phenotype. Finally, bioinformatics analysis of GEPIA and TCGA databases, demonstrated that PARP1 mRNA is higher in CC than in normal tissues and that increased PARP1 mRNA expression levels are associated with poor prognosis of LACC patients. Overall, our data open new opportunities for the development of personalized treatments in women diagnosed with CC.

Highlights

Worldwide, cervical cancer (CC) is the fourth most frequent cancer in women, representing 7.7% of all female cancer deaths [1]
Previous studies reported an implication of signal transducer and activator of transcription 1 (STAT1) in the DNA damage response (DDR), with STAT1 activation observed upon exposure of tumor cells to genotoxic insult [11, 28, 29]
Findings from the present study are in keeping with these literature data, supporting a model in which STAT1 may improve the efficacy of DNA-damaging treatments, at least partially, by lowering PARP1 levels in tumors

Summary

INTRODUCTION

Cervical cancer (CC) is the fourth most frequent cancer in women, representing 7.7% of all female cancer deaths [1]. Other studies have shown that STAT1 promotes death after DNA damage [11,12,13] In line with these latter evidences, we demonstrated that the functional consequences of STAT1 silencing in radiosensitive (C-4I) or radioresistant (CaSki) CC cells were represented by a decrease in sensitivity to radiation and cisplatin, with increased clonogenicity observed in all treatment conditions. STAT1-mediated control of PARP1 levels in CC cell lines, and its treatment of control and IFN-γ- treated cells with a impact on determining the radiosensitizing effect observed in our proteasome inhibitor (MG-132) confirmed the role of STAT1-. Transcriptional and posttranscriptional levels to modulate PARP1 as shown, MG-132 blocked the decrease in PARP1 levels expression To corroborate these findings, we tested the effect of induced by IFN-γ treatment in CaSki cells.

RESULTS

Raspaglio et al 3

DISCUSSION

Findings

MATERIALS AND METHODS