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

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

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colon / drug effects
  • Colon / metabolism
  • Colon / pathology
  • Colonic Neoplasms / blood supply
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology*
  • Down-Regulation / drug effects*
  • Endoplasmic Reticulum Stress / drug effects
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / pathology
  • Propionates / pharmacology*
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Silver Nitrate / metabolism
  • Tumor Burden / drug effects
  • Unfolded Protein Response / drug effects*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Anti-Inflammatory Agents
  • Heat-Shock Proteins
  • Propionates
  • Vascular Endothelial Growth Factor A
  • Silver Nitrate
  • p-coumaric acid
  • molecular chaperone GRP78