ORCID Profile
0000-0002-4109-7190
Current Organisation
Children's Cancer Institute Australia
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Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.BBAMCR.2015.01.021
Abstract: Iron is a crucial transition metal for virtually all life. Two major destinations of iron within mammalian cells are the cytosolic iron-storage protein, ferritin, and mitochondria. In mitochondria, iron is utilized in critical anabolic pathways, including: iron-storage in mitochondrial ferritin, heme synthesis, and iron-sulfur cluster (ISC) biogenesis. Although the pathways involved in ISC synthesis in the mitochondria and cytosol have begun to be characterized, many crucial details remain unknown. In this review, we discuss major aspects of the journey of iron from its initial cellular uptake, its modes of trafficking within cells, to an overview of its downstream utilization in the cytoplasm and within mitochondria. The understanding of mitochondrial iron processing and its communication with other organelles/subcellular locations, such as the cytosol, has been elucidated by the analysis of certain diseases e.g., Friedreich's ataxia. Increased knowledge of the molecules and their mechanisms of action in iron processing pathways (e.g., ISC biogenesis) will shape the investigation of iron metabolism in human health and disease.
Publisher: Oxford University Press (OUP)
Date: 13-05-2013
Abstract: The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is negatively correlated with tumor progression in multiple neoplasms, being a promising new target for cancer treatment. However, the precise molecular effects of NDRG1 remain unclear. Herein, we summarize recent advances in understanding the impact of NDRG1 on cancer metastasis with emphasis on its interactions with the key oncogenic nuclear factor-kappaB, phosphatidylinositol-3 kinase hosphorylated AKT/mammalian target of rapamycin and Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways. Recent studies demonstrating the inhibitory effects of NDRG1 on the epithelial-mesenchymal transition, a key initial step in metastasis, TGF-β pathway and the Wnt/β-catenin pathway are also described. Furthermore, NDRG1 was also demonstrated to regulate molecular motors in cancer cells, leading to inhibition of F-actin polymerization, stress fiber formation and subsequent reduction of cancer cell migration. Collectively, this review summarizes the underlying molecular mechanisms of the antimetastatic effects of NDRG1 in cancer cells.
Publisher: Mary Ann Liebert Inc
Date: 20-10-2020
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.BBAGEN.2017.10.009
Abstract: The cyclin-dependent kinase inhibitor, p21, is well known for its role in cell cycle arrest. Novel anti-cancer agents that deplete iron pools demonstrate marked anti-tumor activity and are also active in regulating p21 expression. These agents induce p21 mRNA levels independently of the tumor suppressor, p53, and differentially regulate p21 protein expression depending on the cell-type. Several chelators, including an analogue of the potent anti-tumor agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), have entered clinical trials, and thus, their molecular mechanism of action is crucial to assess. Hence, this investigation examined how several iron chelators transcriptionally regulate p21. Promoter-deletion constructs luciferase assays RT-PCR western analysis gene silencing co-immunoprecipitation. The transcriptional regulation of the p21 promoter by iron chelators was demonstrated to be dependent on the chelator and cell-type examined. The potent anti-cancer chelator, Dp44mT, induced p21 promoter activity in SK-MEL-28 melanoma cells, but not in MCF-7 breast cancer cells. Further analysis of the p21 promoter identified a 50-bp region between -104 and -56-bp that was required for Dp44mT-induced activation in SK-MEL-28 cells. This region contained several Sp1-binding sites and mutational analysis of this region revealed the Sp1-3-binding site played a significant role in Dp44mT-induced activation of p21. Further, co-immunoprecipitation demonstrated that Dp44mT induced a marked increase in the interactions between Sp1 and the transcription factors, estrogen receptor-α and c-Jun. Dp44mT-induced p21 promoter activation via the Sp1-3-binding site and increased Sp1/ER-α and Sp1/c-Jun complex formation in SK-MEL-28 cells, suggesting these complexes were involved in p21 promoter activation.
Publisher: Elsevier BV
Date: 2016
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.BBAGEN.2018.06.004
Abstract: Polyamines are ubiquitous positively charged amines found in all organisms. These molecules play a crucial role in many biological functions including cell growth, gene regulation and differentiation. The three major polyamines produced in all mammalian cells are putrescine, spermidine and spermine. The intracellular levels of these polyamines depend on the interplay of the biosynthetic and catabolic enzymes of the polyamine and methionine salvage pathway, as well as the involvement of polyamine transporters. Polyamine levels are observed to be high in cancer cells, which contributes to malignant transformation, cell proliferation and poor patient prognosis. Considering the critical roles of polyamines in cancer cell proliferation, numerous anti-polyaminergic compounds have been developed as anti-tumor agents, which seek to suppress polyamine levels by specifically inhibiting polyamine biosynthesis, activating polyamine catabolism, or blocking polyamine transporters. However, in terms of the development of effective anti-cancer therapeutics targeting the polyamine system, these efforts have unfortunately resulted in little success. Recently, several studies using the iron chelators, O-trensox and ICL670A (Deferasirox), have demonstrated a decline in both iron and polyamine levels. Since iron levels are also high in cancer cells, and like polyamines, are required for proliferation, these latter findings suggest a biochemically integrated link between iron and polyamine metabolism.
Publisher: Hindawi Limited
Date: 07-04-2019
DOI: 10.1155/2019/6392763
Abstract: The mitochondrion is an essential organelle important for the generation of ATP for cellular function. This is especially critical for cells with high energy demands, such as neurons for signal transmission and cardiomyocytes for the continuous mechanical work of the heart. However, deleterious reactive oxygen species are generated as a result of mitochondrial electron transport, requiring a rigorous activation of antioxidative defense in order to maintain homeostatic mitochondrial function. Indeed, recent studies have demonstrated that the dysregulation of antioxidant response leads to mitochondrial dysfunction in human degenerative diseases affecting the nervous system and the heart. In this review, we outline and discuss the mitochondrial and oxidative stress factors causing degenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Friedreich’s ataxia. In particular, the pathological involvement of mitochondrial dysfunction in relation to oxidative stress, energy metabolism, mitochondrial dynamics, and cell death will be explored. Understanding the pathology and the development of these diseases has highlighted novel regulators in the homeostatic maintenance of mitochondria. Importantly, this offers potential therapeutic targets in the development of future treatments for these degenerative diseases.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 03-2018
Publisher: BMJ
Date: 08-06-2013
DOI: 10.1136/JCLINPATH-2013-201692
Abstract: N-myc downstream regulated gene 1 (NDRG1) has been well characterised to act as a metastatic suppressor in a number of human cancers. It has also been implicated to have a significant function in a number of physiological processes such as cellular differentiation and cell cycle. In this review, we discuss the role of NDRG1 in cancer pathology. NDRG1 was observed to be downregulated in the majority of cancers. Moreover, the expression of NDRG1 was found to be significantly lower in neoplastic tissues as compared with normal tissues. The most important function of NDRG1 in inhibiting tumour progression is associated with its ability to suppress metastasis. However, it has also been shown to have important effects on other stages of cancer progression (primary tumour growth and angiogenesis). Recently, novel iron chelators with selective antitumour activity (ie, Dp44mT, DpC) were shown to upregulate NDRG1 in cancer cells. Moreover, Dp44mT showed its antimetastatic potential only in cells expressing NDRG1, making this protein an important therapeutic target for cancer chemotherapy. This observation has led to increased interest in the examination of these novel anticancer agents.
Publisher: MDPI AG
Date: 31-03-2015
DOI: 10.3390/NU7042274
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.PHRS.2017.01.009
Abstract: Autophagy is an evolutionary conserved cellular catabolic degradation process in response to stress which involves lysosomal degradation of unnecessary or damaged organelles and misfolded proteins. This is primarily a pro-survival pathway providing the cell with essential nutrients during stressful conditions. There are number of essential metal ions, which are required for normal physiological functioning of cells. Studies have shown that autophagy can be regulated by cellular metal ion concentrations. On the other hand, autophagy is also shown to regulate intracellular levels of certain metal ions. This review discusses recent advances in the research examining the role of metal ions in the autophagic pathway.
Publisher: Impact Journals, LLC
Date: 10-04-2015
Abstract: N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.
Publisher: Elsevier BV
Date: 04-2014
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.BBAGEN.2019.06.007
Abstract: Multi-drug resistance (MDR) is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Moreover, the tumor micro-environment is essential to the formation of drug resistant cancers. Recent evidence indicates that the tumor micro-environment is a critical regulator of cancer progression, distant metastasis and acquired resistance of tumors to various therapies. Despite significant advances in chemotherapy and radiotherapy, the development of therapeutic resistance leads to reduced drug efficacy. This review highlights mechanistic aspects of the biochemistry of the tumor micro-enviroment, such as the hypoglycaemia, reactive oxygen species (ROS), hypoxia and their effects in propagating MDR. This is achieved through: (A) increased survival via autophagy and failure of apoptosis (B) altered metabolic processing and (C) reduction in drug delivery and uptake or increased drug efflux. The development of MDR in cancer has been demonstrated to be majorly influenced by naturally occurring stressors within the tumor micro-environment, as well as chemotherapeutics. Thus, the tumor micro-environment is currently emerging as a major focus of research which needs to be carefully addressed before cancer can be successfully treated. Elucidating the biochemical mechanisms which promote MDR is essential in development of effective therapeutics that can overcome these acquired defences in cancer cells.
No related grants have been discovered for Dong-Hun Bae.