Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis

Abstract

BackgroundWe and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E2)-induced growth of breast cancer cells. We demonstrated that E2-induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R).MethodsThe breast cancer cell lines MCF-7 and BT474 were used as ER(+) cell culture models. Thieno[2,3-c]isoquinolin-5-one (TIQ-A) and olaparib (AZD2281) were used as potent inhibitors of PARP. PARP-1 knockdown by shRNA was used to show specificity of the effects to PARP-1.ResultsIn this study, we aimed to determine the effect of PARP inhibition on estrogen-induced growth of breast cancer cells and examine whether the potential effect is linked to PDZK1 and IGF-1R expression. Our results show that PARP inhibition pharmacologically by TIQ-A or olaparib or by PARP-1 knockdown blocked E2-dependent growth of MCF-7 cells. Such inhibitory effect was also observed in olaparib-treated BT474 cells. The effect of PARP inhibition on cell growth coincided with an efficient reduction in E2-induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E2-induced PDZK1 at the mRNA level. Such regulation may be linked to a modulation of IGF-1R as PARP inhibition pharmacologically or by PARP-1 knockdown efficiently reduced E2-induced expression of the receptor at the protein and mRNA levels.ConclusionsOverall, our results show for the first time that PARP regulates E2-mediated cell growth by controlling the ER/IGF-1R/PDZK1 axis. These findings suggest that the relationship between ER, PDZK1, and IGF-1R may be perturbed by blocking PARP function and that PARP inhibitors may be considered in clinical trials on ER(+) cancers.

The role of NFκB in spheroid formation of human breast cancer cells cultured on the Random Positioning Machine

“…MCF-7 cells had been already treated with olaparib in earlier studies and three different doses were tested (2.5, 5 and 10 µM) 64 . Recent data suggested that PARP inhibitors might be useful to treat estrogen receptor-positive and estrogen-dependent tumors 65 . Here we could show that targeting PARP1/2 with olaparib did not alter the 3D aggregation of the MCF-7 cells cultured on the RPM, which indicated that PARP seems not to be the main key factor responsible for 3D spheroids formation in simulated microgravity.…”

Silencing of ZRF1 impedes survival of estrogen receptor positive MCF-7 cells and potentiates the effect of curcumin

“…BCL2 is an anti-apoptotic protein and plays an oncogenic role in MCF-7 cancer cells [32]. Earlier reports suggest that estrogenic signalling regulates BCL2 on direct interaction at the coding region; whereas, it regulates PARP via IGF-1/PDZK axis in breast cancer cells [33,34]. So this made BCL2 and PARP an interesting choice for investigation on the induction of apoptosis in the context of ZRF1, as it is also regulated by estrogenic signalling.…”

Research Progress on PARP14 as a Drug Target

“…There is evidence that PARP1 regulates estrogen-dependent breast cancer cell growth through the modulation of the estrogen receptor (ER)-insulin-like growth factor 1 receptor (IGF-1R)-Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1) axis. Thus, PARP inhibitors may be powerful weapons for the therapy of ER-positive cancers (Kim et al, 2015 ).…”