MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells

Abstract

Therapies targeting epigenetic changes for cancer treatment are in Phase I/II trials; however, all of these target only nuclear DNA. Emerging evidence suggests presence of methylation marks on mitochondrial DNA (mtDNA); but their contribution in cancer is unidentified. Expression of genes encoded on mtDNA are altered in cancer cells, along with increased glycolytic flux. Such glycolytic flux and elevated reactive oxygen species is supported by increased antioxidant; glutathione. MicroRNA-34a can translocate to mitochondria, mediate downstream apoptotic effects of tumor suppressor P53, and inhibit the antioxidant response element Nrf-2, resulting in depleted glutathione levels. Based on such strong rationale, we encapsulated microRNA-34a in our well-established Hyaluronic-Acid nanoparticles and delivered to cisplatin-sensitive and cisplatin-resistant A549-lung adenocarcinoma cells. Successful delivery and uptake in cells resulted in altered ATP levels, decreased glycolytic flux, Nrf-2 and glutathione levels, ultimately resulting in caspase-3 activation and apoptosis. Most important were the concurrent underlying molecular changes in epigenetic status of D-loop on the mtDNA and transcription of mtDNA-encoded genes. Although preliminary, we provide a novel therapeutic approach in form of altered mitochondrial bioenergetics and redox status of cancer cells with underlying changes in epigenetic status of mtDNA that can subsequently results in induction of cancer cell apoptosis.

miRNA Regulation of Glutathione Homeostasis in Cancer Initiation, Progression and Therapy Resistance

“…In another study, it has been recently demonstrated that miRNA-34 encapsulated in hyaluronic acid nanoparticles is able to reduce intracellular GSH levels and Nrf2 expression, thus sensitizing Non-Small-Cell Lung Carcinoma (NSCLC) cells to the cytotoxic effects of cisplatin [ 150 ].…”

RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory

“…The activities of NAG and acid phosphatase enzymes in hippocampal sections were measured using colorimetric analysis with commercial kits available from Abcam and Biovision, respectively. The LAMP1, LAMP2, NAG and acid phosphatase gene expression levels were measured using qPCR as described previously ( Trivedi et al, 2017 ). Protein expression was evaluated using western blot as previously described ( Talekar et al, 2016 ).…”

Strategic targeting of non‐small‐cell lung cancer utilizing genetic material‐based delivery platforms of nanotechnology

“…Solid lipid nanoparticles, neutral lipid nanoparticles, hyaluronic acid nanoparticles [30][31][32] miR-29b Cationic lipoplex nanoparticles [32] iNOP-7-PLK1 siRNA (polo-like kinase 1 siRNA) Nanoparticle-7 (iNOP-7, a highly branched generation four poly-L-lysine dendrimer [33] long-circulating siRNA Cationic lipid/solid polymer hybrid [34] TUSC2-expressing plasmid DNA Nanovesicles of N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP):cholesterol (DOTAP:chol) [35] Plasmid DNA Liposomal nanoparticles containing cationic lipid, 6-lauroxyhexyl lysinate (LHLN) [36] p53-EGFP plasmid DNA Solid lipid NPs composed of 3β-[N-(Nʹ,Nʹ-dimethyla-minoethane)-carbamoyl]cholesterol hydrochloride (DC-Chol), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and Tween 80 [37] EGFP plasmid DNA Lecithin-based SNLs [37] 2ʹ-O-methyl-RNA (AON) Chitosan-modified PLGA nanoparticles [38] miR-497 Exosomal vehicles ii) Polymeric nanomaterials Polymeric nanomaterials can be synthesized using synthetic or natural polymers, showing diversity in their shape, size, and structure. They can be formed using one of the two methods, that is, precipitation or emulsion method through self-assembly of the co-polymers, which greatly affect their physiochemical properties.…”