A New Histone Deacetylase Inhibitor, MHY4381, Induces Apoptosis via Generation of Reactive Oxygen Species in Human Prostate Cancer Cells

Sachan, Richa; Dey, Prasanta Kumar; Park, Chaeun; Yang, Jungho; Son, Ji Yeon; Park, Jae Hyeon; Lee, Sang Ho; Ahn, Mee‐Young; Kim, In Su; Moon, Hyung Ryong; Kim, Hyung Sik

doi:10.4062/biomolther.2019.074

Cited by 20 publications

(12 citation statements)

References 49 publications

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“…However, the question remains as to whether the increased intracellular iron levels proceed ROS accumulation during EMT, or if high levels of ROS are disrupting Fe–S cluster synthesis to increase IRP mRNA binding to ultimately promote mesenchymal cell iron accumulation. Moreover, because both HDAC inhibitor treatment and alterations in cellular iron availability can promote apoptosis, which in turn can elicit ROS generation in mitochondria [ 26 , 28 , 29 ], future studies should seek to mechanistically determine how HDAC inhibitor treatment augments cell death following ferroptosis induction.…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells

et al. 2021

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Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells

et al. 2021

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“…A recent study showed that abrogation of apoptosome-mediated caspase activation and defective release of Cyt c from the mitochondria are associated with prostate cancer aggressiveness observed in African American men [ 62 ], further supporting an important role of Cyt c as a cancer driver. Other studies have shown that acetyltransferases mediating protein acetylation are upregulated in prostate cancer [ 63 , 64 ] and could be established as rational therapeutic targets [ 65 , 66 ]. Therefore, a better mechanistic understanding of Cyt c acetylation in prostate cancer and potentially other cancers may allow the development of novel effective cancer therapeutics that target Cyt c for the first time.…”

Section: Discussionmentioning

confidence: 99%

Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

Bazylianska

Kalpage

Wan

et al. 2021

Cells

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Prostate cancer is the second leading cause of cancer-related death in men. Two classic cancer hallmarks are a metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. Cytochrome c (Cytc) is at the intersection of both pathways, as it is essential for electron transport in mitochondrial respiration and a trigger of intrinsic apoptosis when released from the mitochondria. However, its functional role in cancer has never been studied. Our data show that Cytc is acetylated on lysine 53 in both androgen hormone-resistant and -sensitive human prostate cancer xenografts. To characterize the functional effects of K53 modification in vitro, K53 was mutated to acetylmimetic glutamine (K53Q), and to arginine (K53R) and isoleucine (K53I) as controls. Cytochrome c oxidase (COX) activity analyzed with purified Cytc variants showed reduced oxygen consumption with acetylmimetic Cytc compared to the non-acetylated Cytc (WT), supporting the Warburg effect. In contrast to WT, K53Q Cytc had significantly lower caspase-3 activity, suggesting that modification of Cytc K53 helps cancer cells evade apoptosis. Cardiolipin peroxidase activity, which is another proapoptotic function of the protein, was lower in acetylmimetic Cytc. Acetylmimetic Cytc also had a higher capacity to scavenge reactive oxygen species (ROS), another pro-survival feature. We discuss our experimental results in light of structural features of K53Q Cytc, which we crystallized at a resolution of 1.31 Å, together with molecular dynamics simulations. In conclusion, we propose that K53 acetylation of Cytc affects two hallmarks of cancer by regulating respiration and apoptosis in prostate cancer xenografts.

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“…Cells that show clear synergistic cell death upon treatment with auranofin and R428, such as the MDA-MB-231, MCF-7, PC-3, and Hep3B cells, are known to have low levels of NRF2 activity. In contrast, the HeLa and H520 cells have relatively higher NRF2 activity ( Zhang et al ., 2010 ; Cazanave et al ., 2014 ; Mine et al ., 2014 ; Lu et al ., 2017 ; Richa et al ., 2020 ). Since the synergistic effect of auranofin and R428 is expected to enhance ROS production, it is presumed that the effect of the combination treatment might be weak in the NRF2-activated cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Induction of Apoptosis by the Combination of an Axl Inhibitor and Auranofin in Human Breast Cancer Cells

Ryu

Shin

et al. 2020

Biomolecules & Therapeutics

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Axl receptor tyrosine kinase has been implicated in cancer progression, invasion, and metastasis in various cancer types. Axl overexpression has been observed in many cancers, and selective inhibitors of Axl, including R428, may be promising therapeutic agents for several human cancers, such as breast, lung, and pancreatic cancers. Here, we examined the cell growth inhibition mediated by R428 and auranofin individually as well as in combination in the human breast cancer cell lines MCF-7 and MDA-MB-231 to identify new advanced combination treatments for human breast cancer. Our data showed that combination therapy with R428 and auranofin markedly inhibited cancer cell proliferation. Isobologram analyses of these cells indicated a clear synergism between R428 and auranofin with a combination index value of 0.73. The combination treatment promoted apoptosis as indicated by caspase 3 activation and poly (ADP-ribose) polymerase cleavage. Cancer cell migration was also significantly inhibited by this combination treatment. Moreover, we found that combination therapy significantly increased the expression level of Bax, a mitochondrial proapoptotic factor, but decreased that of the X-linked inhibitor of apoptosis protein. Furthermore, the suppression of cell viability and induction of Bax expression by the combination treatment were recovered by treatment with N-acetylcysteine. In conclusion, our data demonstrated that combined treatment with R428 and auranofin synergistically induced apoptosis in human breast cancer cells and may thus serve as a novel and valuable approach for cancer therapy.

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A New Histone Deacetylase Inhibitor, MHY4381, Induces Apoptosis via Generation of Reactive Oxygen Species in Human Prostate Cancer Cells

Cited by 20 publications

References 49 publications

HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells

HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells

Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

Synergistic Induction of Apoptosis by the Combination of an Axl Inhibitor and Auranofin in Human Breast Cancer Cells

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