Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells

Abstract

Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel.

Integrative proteomic and microRNA analysis of the priming phase during rat liver regeneration

“…named PAR-4, prostate apoptosis response-4) is a key regulator of cancer cell survival, and the mechanisms of PAR-4 apoptosis induction involves activation of the Fas-FADD-caspase-8 apoptotic pathway, including the translocation of Fas/FasL to the plasma membrane and inhibition of BCL-2 and pro-survival factor NF-κB (Chakraborty et al, 2001). Another study reported that the inhibition of cell proliferation promoted by PAR-4 might be mediated by the ERK1/2 pathway (Pereira et al, 2013). KPNA4 (karyopherin alpha 4, importin alpha 3) regulated angiogenesis and VEGF expression (Ahluwalia et al, 2014).…”

Genomic signatures for paclitaxel and gemcitabine resistance in breast cancer derived by machine learning

“…This SVM contains 8 paclitaxel resistance genes. Predictions of docetaxel sensitivity might be improved by rederiving a specific SVM using taxane pathway genes (Oshiro et al., 2009), and those known to be associated with resistance to doclitaxel (such as CYP1B1 (Chang et al., 2015; Cui et al., 2015), miR‐141 or EIF4E (Yao et al., 2015), DKK3 (Tao et al., 2015), ABCB1 (Hansen et al., 2015; Kato et al., 2015), BIRC5 (Ghanbari et al., 2014), ABCC10 (Domanitskaya et al., 2014), miR‐452 (Hu et al., 2014), and PAWR (Pereira et al., 2013)). The approach that we have introduced could aid in rational selection of other therapeutic regimens that evade or at least minimize the effects of chemoresistance.…”

Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

“…It has been demonstrated that inhibition of MAPK using different inhibitors, including U0126, can restore PAR-4 protein level [18, 74]. Another article indicated a similar effect where MCF-7 breast cancer cells overexpressing Par-4 showed a reduced level of phosphorylation for ERK 1/2 [75]. Ras can also activate the PI3K pathway, however, studies have shown that Ras regulation of Par-4 was not dependent on this survival pathway [18, 74].…”