Pentagalloyl glucose inhibits TNF\u2010\u03b1\u2010activated CXCL1/GRO-\u03b1 expression and induces apoptosis\u2010related genes in triple-negative breast cancer cells

Patricia Mendonca,Sumaih Alghamdi,Karam F A Soliman,Samia Messeha

doi:10.1038/s41598-021-85090-z

Patricia Mendonca, Sumaih Alghamdi + Show 2 more

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https://doi.org/10.1038/s41598-021-85090-z

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Abstract

In triple-negative breast cancer (TNBC), the tumor microenvironment is associated with increased proliferation, suppressing apoptotic mechanisms, an altered immune response, and drug resistance. The current investigation was designed to examine the natural compound pentagalloyl glucose (PGG) effects on TNF-α activated TNBC cell lines, MDA-MB-231 and MDA-MB-468. The results obtained showed that PGG reduced the expression of the cytokine GRO-α/CXCL1. PGG also inhibited IƙBKE and MAPK1 genes and the protein expression of IƙBKE and MAPK, indicating that GRO-α downregulation is possibly through NFƙB and MAPK signaling pathway. PGG also inhibited cell proliferation in both cell lines. Moreover, PGG induced apoptosis, modulating caspases, and TNF superfamily receptor genes. It also augmented mRNA of receptors DR4 and DR5 expression, which binds to TNF-related apoptosis-induced ligand, a potent and specific stimulator of apoptosis in tumors. Remarkably, PGG induced a 154-fold increase in TNF expression in MDA-MB-468 compared to a 14.6-fold increase in MDA-MB-231 cells. These findings indicate PGG anti-cancer ability in inhibiting tumor cell proliferation and GRO-α release and inducing apoptosis by increasing TNF and TNF family receptors' expression. Thus, PGG use may be recommended as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.

Highlights

Abbreviations ATCC American type culture collection breast cancer (BC) Breast cancer BIRC3 Baculoviral inhibitors of apoptosis proteins (IAP) repeat containing 3 BNIP3 BCL2 interacting protein 3 CXCL1 C-X-C motif ligand 1 CXCR2 C-X-C motif receptor 2 DMEM Dulbecco’s modified eagle medium DMSO Dimethyl sulfoxide DR Death receptor estrogen receptor (ER) Estrogen receptor fetal bovine serum heat-inactivated (FBS-HI) Fetal bovine serum heat-inactivated growth-related oncogene (GRO)-α Growth-regulated oncogene-alpha MM-231 MDA-MB-231 MM-468 MDA-MB-468 pentagalloyl glucose (PGG) Pentagalloyl glucose PI3K/AKT Phosphatidylinositol-3-kinases
The IC50 of 50.23 ± 2.16 μM for MM-231 and 35.72 ± 0.75 μM for MM-468 indicate that PGG affects the cell lines differently, inducing more significant cytotoxicity in MM-468 cells (Fig. 1A)
Comparing tumor necrosis factor (TNF)-α-treated cells and the ones that received the co-treatment, the results demonstrated that PGG inhibitory effect was higher in MM-468, presenting a 20-fold decrease in the expression of GRO-α compared to a twofold in MM-231 cells (Fig. 3A)

Summary

Introduction

Abbreviations ATCC American type culture collection BC Breast cancer BIRC3 Baculoviral IAP repeat containing 3 BNIP3 BCL2 interacting protein 3 CXCL1 C-X-C motif ligand 1 CXCR2 C-X-C motif receptor 2 DMEM Dulbecco’s modified eagle medium DMSO Dimethyl sulfoxide DR Death receptor ER Estrogen receptor FBS-HI Fetal bovine serum heat-inactivated GRO-α Growth-regulated oncogene-alpha MM-231 MDA-MB-231 MM-468 MDA-MB-468 PGG Pentagalloyl glucose PI3K/AKT Phosphatidylinositol-3-kinases. One of the most significant challenges in treating this disease is chemotherapeutic resistance It is well-known that chemotherapeutic resistance in BC is associated with abnormal growth factor signaling and aberrant hormonal response. The tumor microenvironment (TME), observed in TNBC, is linked to increased cell proliferation, migration, angiogenesis, suppression of apoptotic mechanisms, an altered immune response, and drug resistance. NFƙB and MAPK signaling regulate several genes associated with inflammatory processes and cancer, controlling cell proliferation and survival, chronic inflammation, apoptosis, and the conversion to cancer c ells[20]. Considering the cytokines’ critical function in cancer cell proliferation, metastasis, and angiogenesis, this study hypothesized that PGG would inhibit cytokines’ expression, leading to reduced cell proliferation and induction of apoptosis through the modulation of the expression of apoptotic-associated genes. Since the genetic variability of TNBCs contributes significantly to the tumor’s microenvironment, the current study evaluated PGG effects on two distinct genetically different TNBC cell lines, MDA-MB-231 (MM-231) and MDA-MB-468 (MM-468) cells

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