ABSTRACT
Acquired platinum resistance poses a significant therapeutic impediment to ovarian cancer patient care, accounting for more than 200,000 deaths annually worldwide. We previously identified that overexpression of the antioxidant superoxide dismutase 1 (SOD1) in ovarian cancer is associated with a platinum-resistant phenotype via conferring oxidative stress resistance against platinum compounds. We further demonstrated that enzymatic inhibition using small-molecule inhibitors or silencing of SOD1 via RNA interference (RNAi) increased cisplatin sensitivity and potency in vitro. We launched this study to explore the potential therapeutic applications of SOD1 silencing in vivo in order to reverse cisplatin resistance using a graphene-based siRNA delivery platform. PEGylated graphene oxide (GO) polyethyleneimine (GOPEI-mPEG) nanoparticle was complexed with SOD1 siRNA. GOPEI-mPEG-siSOD1 exhibited high biocompatibility, siRNA loading capacity, and serum stability, and showed potent downregulation of SOD1 mRNA and protein levels. We further observed that cisplatin and PEI elicited mitochondrial dysfunction and transcriptionally activated the mitochondrial unfolded protein response (UPRmt) used as a reporter for their respective cytotoxicities. SOD1 silencing was found to augment cisplatin-induced cytotoxicity resulting in considerable tumour growth inhibition in cisplatin-sensitive A2780 and cisplatin-resistant A2780DDP subcutaneous mouse xenografts. Our study highlights the potential therapeutic applicability of RNAi-mediated targeting of SOD1 as a chemosensitizer for platinum-resistant ovarian cancers.
Subject(s)
Antineoplastic Agents , Graphite , Nanoparticles , Ovarian Neoplasms , Humans , Female , Animals , Mice , Cisplatin/pharmacology , Cisplatin/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , RNA Interference , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Superoxide Dismutase-1/therapeutic use , Graphite/metabolism , Graphite/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Polyethylene Glycols , RNA, Small Interfering/genetics , Carcinoma, Ovarian Epithelial/geneticsABSTRACT
With 296 million cases estimated worldwide, chronic hepatitis B virus (HBV) infection is the most common risk factor for hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key multifunctional regulatory protein, drives viral replication and interferes with several cellular signalling pathways that drive virus-associated hepatocarcinogenesis. This review article provides a comprehensive overview of the role of HBx in modulating the various hallmarks of HCC by supporting tumour initiation, progression, invasion and metastasis. Understanding HBx-mediated dimensions of complexity in driving liver malignancies could provide the key to unlocking novel and repurposed combinatorial therapies to combat HCC.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B, Chronic , Liver Neoplasms , Trans-Activators , Viral Regulatory and Accessory Proteins , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , Hepatitis B virus/metabolism , Hepatitis B, Chronic/complications , Humans , Liver Neoplasms/pathology , Liver Neoplasms/virology , Trans-Activators/metabolism , Viral Regulatory and Accessory Proteins/metabolismABSTRACT
Epidemiological data consistently rank hepatocellular carcinoma (HCC) as one of the leading causes of cancer-related deaths worldwide, often posing severe economic burden on health care. While the molecular etiopathogenesis associated with genetic and epigenetic modifications has been extensively explored, the biological influence of the emerging field of epitranscriptomics and its associated aberrant RNA modifications on tumorigenesis is a largely unexplored territory with immense potential for discovering new therapeutic approaches. In particular, the underlying cellular mechanisms of different hallmarks of hepatocarcinogenesis that are governed by the complex dynamics of m6A RNA methylation demand further investigation. In this review, we reveal the up-to-date knowledge on the mechanistic and functional link between m6A RNA methylation and pathogenesis of HCC.
