scholarly journals Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Colin W. Garvie ◽  
Xiaoyun Wu ◽  
Malvina Papanastasiou ◽  
Sooncheol Lee ◽  
James Fuller ◽  
...  
Keyword(s):  
Cell Death ◽  
Complex Formation ◽  
Cancer Cells ◽  
Active Site ◽  
Alpha Helix ◽  
Rnase Activity ◽  
Cancer Therapies ◽  
Cancer Cell Death ◽  
New Cancer Therapies ◽  
Related Compounds

AbstractDNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.

scholarly journals Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ding Yan ◽  
Xiaofen Li ◽  
Qianqian Yang ◽  
Qingtian Huang ◽  
Leyi Yao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lung Cancer Cells ◽  
Cancer Therapies ◽  
Metal Compounds ◽  
Cancer Cell Death ◽  
Bax Protein ◽  
Synthetic Derivative

AbstractDeubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

Magneto Mitochondrial Dysfunction Mediated Cancer Cell Death Using Intracellular Magnetic Nano-Transducers

2021 ◽  
Author(s):  
Wooram Park ◽  
Seok-Jo Kim ◽  
Paul Cheresh ◽  
Jeanho Yun ◽  
Byeongdu Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Cancer Cell ◽  
High Sensitivity ◽  
Intrinsic Pathway ◽  
Cancer Cell Death

Mitochondria are crucial regulators of the intrinsic pathway of cancer cell death. The high sensitivity of cancer cells to mitochondrial dysfunction offers opportunities for emerging targets in cancer therapy. Herein,...

scholarly journals Hydrogen Phosphate Selectively Induces MDA-MB-231 Breast Cancer Cell Death in vitro

2021 ◽  
Author(s):  
Aya Shanti ◽  
Kenana Al Adem ◽  
Cesare Stefanini ◽  
Sungmun Lee
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Dihydrogen Phosphate ◽  
Human Breast ◽  
Hydrogen Phosphate ◽  
Cancer Cell Death ◽  
Phosphate Ions

Abstract Phosphate ions are the most abundant anions inside the cells, and they are increasingly gaining attention as key modulators of cellular function and gene expression. However, little is known about the effect of inorganic phosphate ions on cancer cells, particularly breast cancer cells. Here, we investigated the toxicity of different phosphate compounds to triple-negative human breast cancer cells (MDA-MB-231) and compared it to that of human monocytes (THP-1). We found that, unlike dihydrogen phosphate (H2PO4−), hydrogen phosphate (HPO42−) at 20 mM or lower concentrations induced breast cancer (MDA-MB-231) cell death more than immune (THP-1) cell death. We correlate this effect to the fact that phosphate in the form of HPO42− raises pH levels to alkaline levels which are not optimum for transport of phosphate into cancer cells. The results in this study highlight the importance of further exploring hydrogen phosphate (HPO42−) as a potential therapeutic for the treatment of breast cancer.

scholarly journals Immunomodulatory activity of IR700-labelled affibody targeting HER2

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Justyna Mączyńska ◽  
Chiara Da Pieve ◽  
Thomas A. Burley ◽  
Florian Raes ◽  
Anant Shah ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Light Irradiation ◽  
Immunomodulatory Activity ◽  
Her2 Positive ◽  
Immunological Responses ◽  
Cancer Cell Death ◽  
Immature Dendritic Cells

Abstract There is an urgent need to develop therapeutic approaches that can increase the response rate to immuno-oncology agents. Photoimmunotherapy has recently been shown to generate anti-tumour immunological responses by releasing tumour-associated antigens from ablated tumour cell residues, thereby enhancing antigenicity and adjuvanticity. Here, we investigate the feasibility of a novel HER2-targeted affibody-based conjugate (ZHER2:2395-IR700) selectively to induce cancer cell death in vitro and in vivo. The studies in vitro confirmed the specificity of ZHER2:2395-IR700 binding to HER2-positive cells and its ability to produce reactive oxygen species upon light irradiation. A conjugate concentration- and light irradiation-dependent decrease in cell viability was also demonstrated. Furthermore, light-activated ZHER2:2395-IR700 triggered all hallmarks of immunogenic cell death, as defined by the translocation of calreticulin to the cell surface, and the secretion of ATP, HSP70/90 and HMGB1 from dying cancer cells into the medium. Irradiating a co-culture of immature dendritic cells (DCs) and cancer cells exposed to light-activated ZHER2:2395-IR700 enhanced DC maturation, as indicated by augmented expression of CD86 and HLA-DR. In SKOV-3 xenografts, the ZHER2:2395-IR700-based phototherapy delayed tumour growth and increased median overall survival. Collectively, our results strongly suggest that ZHER2:2395-IR700 is a promising new therapeutic conjugate that has great potential to be applicable for photoimmunotherapy-based regimens.

scholarly journals Stage-specific embryonic antigen-3 (SSEA-3) and β3GalT5 are cancer specific and significant markers for breast cancer stem cells

2015 ◽  
Vol 113 (4) ◽  
pp. 960-965 ◽  
Author(s):  
Sarah K. C. Cheung ◽  
Po-Kai Chuang ◽  
Han-Wen Huang ◽  
Wendy W. Hwang-Verslues ◽  
Candy Hsin-Hua Cho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Embryonic Stem ◽  
Cancer Therapies ◽  
New Cancer Therapies ◽  
Globo Series

The discovery of cancer stem cells (CSCs), which are responsible for self-renewal and tumor growth in heterogeneous cancer tissues, has stimulated interests in developing new cancer therapies and early diagnosis. However, the markers currently used for isolation of CSCs are often not selective enough to enrich CSCs for the study of this special cell population. Here we show that the breast CSCs isolated with CD44+CD24-/loSSEA-3+ or ESAhiPROCRhiSSEA-3+ markers had higher tumorigenicity than those with conventional markers in vitro and in vivo. As few as 10 cells with CD44+CD24-/loSSEA-3+ formed tumor in mice, compared with more than 100 cells with CD44+CD24-/lo. Suppression of SSEA-3 expression by knockdown of the gene encoding β-1,3-galactosyltransferase 5 (β3GalT5) in the globo-series pathway, led to apoptosis in cancer cells specifically but had no effect on normal cells. This finding is further supported by the analysis of SSEA-3 and the two related globo-series epitopes SSEA4 and globo-H in stem cells (embryonic stem cells and induced pluripotent stem cells) and various normal and cancer cells, and by the antibody approach to target the globo-series glycans and the late-stage clinical trials of a breast cancer vaccine.

scholarly journals Selective imaging and cancer cell death via pH switchable near-infrared fluorescence and photothermal effects

2016 ◽  
Vol 7 (9) ◽  
pp. 5995-6005 ◽  
Author(s):  
Jingye Zhang ◽  
Zining Liu ◽  
Peng Lian ◽  
Jun Qian ◽  
Xinwei Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Near Infrared ◽  
Near Infrared Fluorescence ◽  
Ph Changes ◽  
Cancer Cell Death ◽  
Photothermal Effects

A theranostic probe is designed that specifically illuminates and photoablates cancer cells by sensing pH changes in the lysosomes and mitochondria.

scholarly journals Mitochondrial Complex I Inhibitors and Forced Oxidative Phosphorylation Synergize in Inducing Cancer Cell Death

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Roberta Palorini ◽  
Tiziana Simonetto ◽  
Claudia Cirulli ◽  
Ferdinando Chiaradonna
Keyword(s):  
Cell Death ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Complex I ◽  
Mitochondrial Complex I ◽  
Low Doses ◽  
Mitochondrial Complex ◽  
Cancer Cell Death ◽  
Glucose Depletion

Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS) for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.

Identification of morpholine based hydroxylamine analogues: selective inhibitors of MARK4/Par-1d causing cancer cell death through apoptosis

2020 ◽  
Vol 44 (38) ◽  
pp. 16626-16637
Author(s):  
Mudasir Nabi Peerzada ◽  
Parvez Khan ◽  
Nashrah Sharif Khan ◽  
Aysha Gaur ◽  
Fernando Avecilla ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Active Site ◽  
Active Site Residues ◽  
Selective Inhibitors ◽  
Cancer Cell Death

Interaction of compound 32 with various active site residues of MARK4.

Fluorinated thiazolidinols cause cell death in A549 lung cancer cells via PI3K/AKT/mTOR and MAPK/ERK signalling pathways

MedChemComm ◽  
2016 ◽  
Vol 7 (6) ◽  
pp. 1197-1203 ◽  
Author(s):  
Ravindra M. Kumbhare ◽  
Tulshiram L. Dadmal ◽  
Dinesh Kumar ◽  
M. Janaki Ramaiah ◽  
Anudeep Kota ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lung Cancer Cells ◽  
Signalling Pathways ◽  
Lung Cancer Cell ◽  
Cancer Cell Death ◽  
A549 Lung Cancer Cell ◽  
A549 Lung

Fluorinated thiazolidinols cause A549 lung cancer cell death by acting via PI3K/Akt/mTOR and MEK/ERK pathways.

scholarly journals Electrochemotherapy Causes Caspase-Independent Necrotic-Like Death in Pancreatic Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1177 ◽  
Author(s):  
Philana Fernandes ◽  
Tracey R. O’Donovan ◽  
Sharon L. McKenna ◽  
Patrick F. Forde
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Patient Survival ◽  
Morphological Changes ◽  
Drug Uptake ◽  
Cancer Therapies ◽  
Pancreatic Cancer Cells ◽  
Membrane Porosity

Pancreatic cancer represents a major challenge in oncology. Poor permeability of the pancreas and resistance to currently available therapies are impediments to improved patient survival. By transiently increasing cell membrane porosity and increasing drug uptake, Electrochemotherapy (ECT) has the potential to overcome these issues. In this study, we have evaluated the response of human and murine pancreatic cancer cells, in vitro, to electroporation in combination with Bleomycin, Cisplatin, or Oxaliplatin (ECT). The cytotoxic actions of all three drugs are potentiated when combined with electroporation in these cells. The biochemical and morphological changes post ECT are associated with immunogenic cell death that occurs with necroptosis rather than apoptosis. Moreover, ECT-induced cell death is rescued by Nec-1 suggesting that necroptosis may play a role in cell death mediated by cancer therapies.

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