Evidence of PKC Binding and Translocation to Explain the Anticancer Mechanism of Chlorogenic Acid in Breast Cancer Cells

Author(s): S. J. Deka, S. Gorai, D. Manna, V. Trivedi*.

Journal Name: Current Molecular Medicine

Volume 17 , Issue 1 , 2017

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Abstract:

Chlorogenic acid (CGA) exhibits potentials towards liver, breast and skin cancer. Cancer cells stimulated with CGA exhibits differential expression of transcriptional factors and regulatory molecules but the molecular target of the molecule is not known. Superposition of biophoric elements of CGA with Curcumin gives maximum common substructure score of 0.90. Molecular modeling studies further suggest that CGA fits into the C1b domain of PKC with extensive interaction with residues lining binding site. It binds PKC in a concentration dependent manner with dissociation constant KD, 28.84±3.95 μM. PKC-CGA complex is stable with minimal distortion to the 3-D structure and maintains the hydrogen bonding between ligand and receptor during simulation period. Cells stimulated with CGA causes 12.1 ± 0.56% PKC translocation from the cytosol to the plasma membrane. It disturbs the cell cycle and arrest the cancer cell at the G1 phase with a reduction in S-phase. Chlorogenic acid exhibits killing of cancer cells in a dose-dependent manner with an IC50 of 75.88 ± 4.54μg/ml and 52.5 ± 4.72μg/ml towards MDAMB-231 and MCF-7 cells respectively. It induces apoptosis in cancer cells as evident by AO/EtBr staining and degradation of genomic DNA to give a laddering pattern. Apoptosis in cancer cells involves mitochondrial pathway as supported by a reduction in mitochondrial potentials and release of cyt-C into the cytosol. Hence, the current study has established PKC as an important signaling molecule to the observed anti-cancer effects of CGA and provides the impetus to design better CGA analogs for improved anti-cancer potential against the malignant tumor.

Keywords: Agonist, cancer, cell-cycle, curcumin, cytochrome-C, docking, mitochondria, protein kinase C, PMA, translocation.

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Article Details

VOLUME: 17
ISSUE: 1
Year: 2017
Page: [79 - 89]
Pages: 11
DOI: 10.2174/1566524017666170209160619
Price: $58

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