Gold nanoparticles (AuNPs) are used enormously in different cancers but very little is known regarding their molecular mechanism and surface charge role in the process of cell death. Here, we elucidate the molecular mechanism by which differentially charged AuNPs induce cytotoxicity in triple negative breast cancer (TNBC) cells. Cytotoxicity assay revealed that both negatively charged (citrate-capped) and positively charged (cysteamine-capped) AuNPs induced cell-death in a dose-dependent manner. We provide first evidence that AuNPs-induced oxidative stress alters Wnt signalling pathway in MDA-MB-231 and MDA-MB-468 cells. Although both differentially charged AuNPs induced cell death, the rate and mechanism involved in the process of cell death were different. Negatively charged AuNPs increased the expression of MKP-1, dephosphorylated and deacetylated histone H3 at Ser10 and K9/K14 residues respectively whereas, positively charged AuNPs decreased the expression of MKP-1, phosphorylated and acetylated histone H3 at Ser 10 and K9/K14 residues respectively. High-resolution transmission electron microscopy (HRTEM) studies revealed that AuNPs were localised in cytoplasm and mitochondria of MDA-MB-231 cells. Interestingly, AuNPs treatment makes MDA-MB-231 cells sensitive to 5-fluorouracil (5-FU) by decreasing the expression of thymidylate synthetase enzyme. This study highlights the role of surface charge (independent of size) in the mechanisms of toxicity and cell death.

Triple negative breast cancer represents an important clinical challenge, as these tumours do not respond to endocrinal therapy. Nanotechnology offers a solution to overcome these clinical challenges. Gold nanoparticles (AuNPs) have been used in multiple ways for the prevention of breast cancer due to their unique physicochemical properties, therapeutic payload efficiency of drugs, biological compatibility, theranostic applications and radiation sensitizer effects. Here, we elucidate the molecular mechanism by which AuNPs selectively cause death in triple negative breast cancer (MDA‐MB‐231) cells. Both citrate capped (negatively charged) and cysteamine capped (positively charged) AuNPs significantly decreased the proliferation of MDA‐MB‐231 cells in a dose‐dependent manner and were less toxic to MCF‐10A cells. For the first time, we provide evidence that AuNPs can be used to prevent the progression of triple negative breast cancer by altering Wnt/β‐catenin signalling. AuNPs significantly decreased the protein expressions of β‐catenin, GSK‐3β, Cyclin D1, p53 and increased the protein expressions of phospho‐GSK‐3β, acetyl‐p53 and p‐p38. HR‐TEM was used to study the localisation of AuNPs. It is interesting to report that both AuNPs caused cell death but (−ve charged) AuNPs significantly increased the expression of MKP‐1, dephosphorylated and deacetylated histone H3 at Ser10 and K9/K14 residues respectively. However, (+ ve charged) AuNPs decreased the expression of MKP‐1, phosphorylated and acetylated histone H3 at Ser10 and K9/K14 residues respectively in MDA‐MB‐231 cells. Although both the nanoparticles have almost similar size (between 25–40 nm), the surface charge of AuNPs might contribute to the different patterns of histone modifications. Phosphorylation of histone H3 at ser 10 has been shown to be involved in chromatin condensation during mitosis and increase in phosphorylation of histone H3 suggests that cells might be undergoing mitotic catastrophy with (+ ve charged) AuNPs. This was reflected in lower IC50 values (655 μg/mL) with (+ ve charged) AuNPs in comparison to (−ve charged) AuNPs (720 μg/mL). To the best of our knowledge, we report for the first time that AuNPs potentiates the cell death of MDA‐MB‐231 cells to 5‐fluorouracil (5‐FU). Studies are in progress to gain insights on the sensitization effect of AuNPs on MDA‐MB‐231 cells to 5‐Fluorouracil. This study further warrants the usage of AuNPs either alone or in combination in cancer therapeutics.Support or Funding InformationThe authors are thankful to NIPER, SAS NAGAR, MOHALI, PUNJAB for funding the current experimental workThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.