The role of NFκB in pentagalloyl glucose inhibition of TNF‐α‐induced CXCL1 expression and induction of apoptosis‐related genes in racially different triple negative breast cancer cells.

Abstract

Drug resistance is the leading cause of breast cancer‐related mortality in women, and triple negative breast cancer (TNBC) is the most aggressive subtype. CXCL1/GRO‐α has been identified as a pro‐inflammatory chemokine overexpressed in breast cancer, promoting angiogenesis and having an increased potential to metastasize. The current study investigated the effect of the naturally occurring polyphenolic compound pentagalloyl glucose (PGG) in TNF‐α‐induced CXCL1 expression in MDA‐MB‐231 (Caucasian) and MDA‐MB‐468 (African American) TNBC cells. In addition, PGG apoptotic effect was evaluated through the study of apoptosis‐related genes in both cell lines. Results showed that PGG inhibited TNF‐α‐stimulated CXCL1 expression in the transcription and protein level in Caucasian and African American TNBC cell lines. Through mRNA quantification analysis, data showed that PGG downregulated IKBKE (expressed in 60.4% of the breast cancer tumors) and MAPK1/ERK2 (expressed in tumor tissues with 5 to 10‐fold increase) expression in both cell lines. Moreover, PGG was more effective in inhibiting IKBKE expression in MDA‐MB‐231 compared to MDA‐MB‐468 (9 and 2‐fold inhibition, respectively). Also, PGG reduced MAPK1 gene expression in 3‐fold in Caucasian and 6‐fold in the African American cells. Gene transcription studies showed that PGG induced expression of the pro‐apoptotic genes BNIP3, BNIP3L, GADD45A, TP53BP2, and RIPK2, which are critical initiators of the intrinsic and extrinsic apoptotic pathways. Although PGG increased the expression of apoptosis‐related genes in both cell lines, there was a significantly higher expression in MDA‐MB‐231 cells (5 to 14.7‐fold) compared to MDA‐MB‐468 cells (2 to 5.8‐fold). Furthermore, BAK1 gene expression was only induced in African American cells showing a 35.7‐fold increase after PGG treatment. The obtained data show that PGG inhibited the expression of CXCL1 pro‐inflammatory chemokine and upregulated the expression of specific pro‐apoptotic genes. It was concluded that PGG might have great potential in target therapy for TNBC.Support or Funding InformationThis work was supported by a grant from the NIH/NIMHD grant U54 007582