Penta‐O‐Galloyl‐β‐D‐Glucose (PGG) Anti‐Proliferative and Pro‐Apoptotic Effect through Up‐Regulation of Tumor Necrosis Factor and its Receptors in Triple Negative Breast Cancer Cells

Abstract

1,2,3,4,6‐Penta‐O‐Galloyl‐β‐D‐Glucose (PGG) is a naturally occurring polyphenolic compound found in many medicinal plants such as Rhus chinensis Mill and Paeonia suffruticosa. PGG potential in chemoprevention has been reported in many cancer studies including lung, prostate, breast, liver, and sarcoma. In mechanistic studies, PGG modulated apoptosis, angiogenesis, metastasis, and signaling pathways. In the present study, we investigated PGG anti‐proliferative and pro‐apoptotic effects in MDA‐MB‐231 (Caucasian) and MDA‐MB‐468 (African American) triple‐negative breast cancer (TNBC) cells; recognized as the most aggressive type of breast cancer with poor prognosis. The results showed that PGG inhibited cell viability of both cell lines in a dose‐dependent manner. Notably, PGG was 5‐fold more potent in African American cells (IC50 35.7 μM) compared to MDA‐MB‐231(IC50 176.1 μM). PGG anti‐proliferative effect was similar to Taxol in concentrations of 50 and 25 μM in MDA‐MB‐231 and MDA‐MB‐468, respectively, demonstrating more effectiveness in African American cells compared to Caucasians. Results obtained from Annexin V/PI flow cytometry showed that PGG treatment induced 42.3% of apoptosis in Caucasian, and 62% in African American breast cancer cells in the concentration of 100 μM. Subsequently, the expression of several genes associated with apoptosis regulation was detected by RT‐PCR assay to explore underlying apoptosis mechanisms. PGG increased mRNA expression of apoptosis genes in 5‐fold or more in both cell lines, inducing the expression of 12 genes in MDA‐MB‐231, versus 5 genes in MDA‐MB‐468 cells. Remarkably, the highest increase was seen in Tumor Necrosis Factor (TNF) expression which presented a 154.6‐fold increase in African American cells, compared to 14.6‐fold in MDA‐MB‐231. TNF Receptor Superfamily Member 10a (TNFRSF10A) expression was also increased in both cell lines; however, TNF Receptor Superfamily Member 9 (TNFRSF9) expression was induced exclusively in MDA‐MB‐231 cells. TNF‐induced apoptosis is known to be mediated through activation of type I receptors, the death domain of which recruits many different signaling proteins, which together are considered part of an apoptotic cascade. Therefore the results suggest that PGG could be a potential inducer of apoptosis in TNBC cells in Caucasian and African American women, by inducing expression of TNF and its receptors and thus offering a promising approach for cancer therapy.Support or Funding InformationThis research was supported by grants received from NIH NIMHD G12‐MD007582 and P20 MD 0006738This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.