Title

Targeting Multiple Pro-Apoptotic Signaling Pathways With Curcumin in Prostate Cancer Cells

Funding Source

National Institute on Minority Health and Health Disparities, Xavier University of Louisiana, National Institutes of Health

Grant Number

G12MD007583, 5G12MD007595, 8G12MD007590

Department

Department of Chemistry

Document Type

Article

Publication Date

6-19-2017

Abstract

Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.

Comments

DOI: 10.1371/journal.pone.0179587

PubMed ID: 28628644

Funding text

This research was supported by NIH grants to the Universidad Central del Caribe Biomedical Proteomics Facility (G12MD007583) (NMB), Xavier University of Louisiana (GW) (5G12MD007595) and Clark Atlanta University (8G12MD007590) from the National Institute on Minority Health and Health Disparities (NIMHD) RCMI Program. The funders had no role in study

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