Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells

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 mechan...

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Bibliographic Details
Published in:	PloS one Vol. 12; no. 6; p. e0179587
Main Authors:	Rivera, Mariela, Ramos, Yanilda, Rodríguez-Valentín, Madeline, López-Acevedo, Sheila, Cubano, Luis A, Zou, Jin, Zhang, Qiang, Wang, Guangdi, Boukli, Nawal M
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 19-06-2017 Public Library of Science (PLoS)
Subjects:	Adenosine diphosphate Analysis Animals Anticancer properties Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Autophagy Biology and Life Sciences Breast cancer Calreticulin Calreticulin - genetics Calreticulin - metabolism Cancer Cancer cells Cancer therapies Caspase 3 - metabolism Cell activation Cell cycle Cell Cycle Checkpoints - drug effects Cell death Cell Line, Tumor Chemotherapy Chromatography, High Pressure Liquid Coupling (molecular) Curcumin Curcumin - pharmacology Cytometry Disease Dosage and administration Down-Regulation - drug effects Drug therapy Endoplasmic reticulum Endoplasmic Reticulum Chaperone BiP Endoplasmic Reticulum Stress - drug effects Flow cytometry Gene expression Glucose Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism Homeostasis Immunology Indicators Inflammation Inositol Kinases Labels Male Markers Marking Medical research Medicine Metastases Molecular modelling Mortality Networks Oxidative stress Oxygen Phagocytosis Polymerase chain reaction Prostate cancer Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein disulfide-isomerase Protein Disulfide-Isomerases - genetics Protein Disulfide-Isomerases - metabolism Protein folding Proteins Proteomics Reactive oxygen species Ribose Signal transduction Signal Transduction - drug effects Stress response Transcription factors Up-Regulation - drug effects Louisiana United States > US Puerto Rico
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Summary:	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.
Bibliography:	Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0179587