Antiproliferative effect of p-Coumaric acid targets UPR activation by downregulating Grp78 in colon cancer
| Autor: | Vinothkumar Rajamanickam, Sharada H. Sharma, Sangeetha Nagarajan |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Vascular Endothelial Growth Factor A Coumaric Acids Colorectal cancer Angiogenesis Colon Anti-Inflammatory Agents Down-Regulation Inflammation Apoptosis Toxicology 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor medicine Animals Humans Rats Wistar Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins Cell Proliferation Membrane Potential Mitochondrial Neovascularization Pathologic Chemistry General Medicine medicine.disease Endoplasmic Reticulum Stress Tumor Burden 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Colonic Neoplasms Unfolded protein response Cancer research Unfolded Protein Response Silver Nitrate Signal transduction medicine.symptom Propionates Signal Transduction |
| Zdroj: | Chemico-biological interactions. 291 |
| ISSN: | 1872-7786 |
| Popis: | p-CA is a naturally occurring phenolic acid present in most plants and in all commonly consumed vegetables and fruits. Here we demonstrated the anti-cancer effect of the food borne phytochemical p-CA both in vitro and in vivo models of colon cancer using growth rate and tumor incidence as endpoints. Glucose regulated protein (GRP78) induction and UPR activation plays a key role in oncogenic progression, therefore increased dependence of cancer cells on these UPR signaling pathways for survival can be exploited for anti-cancer research. Hence we investigated the effect of p-CA on Grp78 a molecular chaperone often upregulated in colon cancer and its impact on unfolded protein response (UPR). Administration of the procarcinogen 1,2- dimethylhydrazine (DMH) causes Grp78 upregulation and tumor adaptation via UPR activation. The adaptive activity of UPR activates antiapoptotic NF-κB that results in upregulation of the markers of inflammation and angiogenesis. Supplementation of p-CA downregulated Grp78 and activated UPR mediated apoptosis both in in vitro and in vivo models of colon cancer. Further we observed that p-CA significantly reduced inflammation by decreasing the expression of cytokines COX-2, IL-6, TNF-α and PGE2 as analyzed by q-PCR and also reduced the expression of p-p65 and p-IκBα as analyzed by western blot. Further mechanistic insights revealed that p-CA inhibits Grp78 upregulation in cancer cells through activation of PERK-eIF2α-ATF-4-CHOP pathway that culminates in apoptosis inducing effect of p-CA. |
| Databáze: | OpenAIRE |
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