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Chem Biol Interact. 2018 Aug 1;291:16-28. doi: 10.1016/j.cbi.2018.06.001. Epub 2018 Jun 5.

Antiproliferative effect of p-Coumaric acid targets UPR activation by downregulating Grp78 in colon cancer.

Author information

1
School of Chemical and Biotechnology, SASTRA Deemed University, Thirumalaisamudram, Thanjavur, 613401, Tamil Nadu, India.
2
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, PR China.
3
School of Chemical and Biotechnology, SASTRA Deemed University, Thirumalaisamudram, Thanjavur, 613401, Tamil Nadu, India. Electronic address: sangeetha@scbt.sastra.edu.

Abstract

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.

KEYWORDS:

Apoptosis; Cancer chemoprevention; Colon cancer; ER stress; Grp78 (78 kDa glucose regulated protein); p-Coumaric acid

PMID:
29879413
DOI:
10.1016/j.cbi.2018.06.001
[Indexed for MEDLINE]

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