Curcumin reduces paclitaxel resistance in ovarian carcinoma cells by upregulating SNIP1 and inhibiting NFκB activity

The therapeutic activity of paclitaxel against ovarian carcinoma is relatively low due to the frequent occurrence of chemoresistance and disease recurrence. We found earlier that a combination of curcumin and paclitaxel reduces cell viability and promotes Apoptosis in paclitaxel-resistant (i.e., taxol-resistant, Txr) ovarian Cancer cells. In the present study, we first used RNA sequencing (RNAseq) analysis to identify genes that are upregulated in Txr cell lines but downregulated by curcumin in ovarian Cancer cells. The nuclear factor kappa B (NFκB) signaling pathway was shown to be upregulated in Txr cells. Furthermore, based on the protein interaction database BioGRID, we found that Smad nuclear interacting protein 1 (SNIP1) may be involved in regulating the activity of NFκB in Txr cells. Accordingly, curcumin upregulated SNIP1 expression, which in turn downregulated the pro-survival genes Bcl-2 and Mcl-1. Using shRNA-guided gene silencing, we found that SNIP1 depletion reversed the inhibitory effect of curcumin on NFκB activity. Moreover, we identified that SNIP1 enhanced NFκB protein degradation, thereby suppressing NFκB/p65 acetylation, which is involved in the inhibitory effect of curcumin on NFκB signaling. The transcription factor early growth response protein 1 (EGR1) was shown to represent an upstream transactivator of SNIP1. Consequently, we show that curcumin inhibits NFκB activity by modulating the EGR1/SNIP1 axis to attenuate p65 acetylation and protein stability in Txr cells. These findings provide a new mechanism to account for the effects of curcumin in inducing Apoptosis and reducing paclitaxel resistance in ovarian Cancer cells.

EGR1; NFκB; SNIP1; curcumin; ovarian cancer; paclitaxel.