Induction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives

Background: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR) has been proposed as potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis. Objective: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives. Methods: Cell proliferation assays were performed on HeLa, Capan1, MCF7, HCC1937, and MRC5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis. Results: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of pro-apoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and -7. Flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, which is also demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells). Conclusion: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways.

Download Full-text

Dihydroartemisinin Exhibits Antitumor Activity Toward Human Gastric Cancer Cells Through the Endoplasmic Reticulum Stress Pathway

10.21203/rs.3.rs-616975/v1 ◽

2021 ◽

Author(s):

Si Chen ◽

Hanlin Wang ◽

Tie Chen ◽

Furong Deng ◽

Hongbin Li ◽

...

Keyword(s):

Gastric Cancer ◽

Flow Cytometry ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Antitumor Activity ◽

Er Stress ◽

Annexin V ◽

Hoechst Staining ◽

Dose Dependent ◽

Stress Pathway

Abstract Background: Gastric cancer is the most fatal digestive tract tumor. The current treatment of gastric cancer often causes adverse effects. Dihydroartemisinin (DHA), a first-line antimalarial drug, is a derivative of a compound from a well-known Chinese medicinal plant Artemisia annua. DHA demonstrates antitumor activities toward many different types of cancer while exerts no apparent adverse effects on normal cells, making it a promising lead compound for cancer treatment. DHA induces apoptosis in Gastric cancer cell line 7901 (SGC-7901). However, the exact mechanism of this antitumor activity remains not fully explored. Methods: A CCK-8 assay to detect cell viability with DHA treatment in gastric cancer SGC-7901. The colony formation was visualized by crystal violet staining. The DHA-treatment cells were stained by Annexin-V FITC/PI dye and then subject to cell flow cytometry. The apoptosis was further observed in the Hoechst staining assay. Real-time qPCR was conducted to detect apoptosis-related markers. Western blotting was conducted to detect the protein levels of the endoplasmic reticulum (ER) stress pathway-related proteins. KIRA6, an ER stress pathway inhibitor was applied to find out whether it could reverse the cell death. Results: DHA induced dose-dependent apoptosis in Gastric SGC-7901 cell with an IC50 of about 4 mg/ mL. It significantly increased the proportion of apoptotic cells in a dose-dependent pattern in the Annexin V/PI flow cytometry. Significantly higher percentages of cells with a more prominently stained nucleus were observed in the Hoechst staining assay. In qPCR assay, the mRNA level of Bcl-2 was significantly decreased while that of Bax was significantly increased in a dose-dependent manner after DHA treatment. In the western blot assay, increased Bax and Bim and decreased Caspase 9, Bcl-2 were observed. Consistently, the levels of pro-apoptotic proteins were increased while those of anti-apoptotic ones were decreased as shown in the Human Apoptosis Array assay after DHA treatment. DHA stimulated the expression of GRP78, ATF4, IRE1, CHOP, and phosphorylated c-Jun (p-c-Jun) as revealed in western blotting. The cell death caused by DHA treatment was reversed by KIRA6. Conclusions: DHA exerts its antitumor activity on SGC-7901 cells through the IRE1/c-Jun ER stress pathway.

Download Full-text

AC-YVAD-CMK Inhibits Pyroptosis and Improves Functional Outcome after Intracerebral Hemorrhage

BioMed Research International ◽

10.1155/2018/3706047 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Xiao Lin ◽

Haotuo Ye ◽

Felix Siaw-Debrah ◽

Sishi Pan ◽

Zibin He ◽

...

Keyword(s):

Cell Death ◽

Intracerebral Hemorrhage ◽

Cell Damage ◽

Neuronal Cell ◽

Neurological Function ◽

Inflammatory Factors ◽

Neuroprotective Effects ◽

Caspase 1 ◽

Cell Death Pathways ◽

Cell Death Pathway

Intracerebral hemorrhage (ICH) refers to bleeding in the brain and is associated with the release of large amount of inflammasomes, and the activation of different cell death pathways. These cell death pathways lead to removal of inactivated and damaged cells and also result in neuronal cell damage. Pyroptosis is a newly discovered cell death pathway that has gained attention in recent years. This pathway mainly depends on activation of caspase-1-mediated cascades to cause cell death. We tested a well-known selective inhibitor of caspase-1, AC-YVAD-CMK, which has previously been found to have neuroprotective effects in ICH mice model, to ascertain its effects on the activation of inflammasomes mediated pyroptosis. Our results showed that AC-YVAD-CMK could reduce caspase-1 activation and inhibit IL-1β production and maturation, but has no effect on NLRP3 expression, an upstream inflammatory complex. AC-YVAD-CMK administration also resulted in reduction in M1-type microglia polarization around the hematoma, while increasing the number of M2-type cells. Furthermore, AC-YVAD-CMK treated mice showed some recovery of neurological function after hemorrhage especially at the hyperacute and subacute stage resulting in some degree of limb movement. In conclusion, we are of the view that AC-YVAD-CMK could inhibit pyroptosis, decrease the secretion or activation of inflammatory factors, and affect the polarization of microglia resulting in improvement of neurological function after ICH.

Download Full-text

EXPERIMENTAL MODELING OF APOPTOSIS UNDER CONDITIONS OF STABLE STRONTIUM EXPOSURE

Medical Immunology (Russia) ◽

10.15789/1563-0625-2019-1-137-140 ◽

2019 ◽

Vol 21 (1) ◽

pp. 137-140

Author(s):

O. V. Dolgikh ◽

N. V. Zaitseva ◽

D. G. Dianova ◽

A. V. Krivtsov ◽

K. D. Starkova ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Death ◽

Programmed Cell Death ◽

Annexin V ◽

Fold Increase ◽

Apoptosis Markers ◽

Stable Strontium ◽

Cell Death Mechanisms ◽

Apoptotic Pathways ◽

And Control

Apoptosis is defined as a highly regulated form of programmed cell death with typical morphological and biochemical features. A variety of factors, including heavy metals, may influence the intensity of programmed cell death. The aim of the work was to simulate apoptosis in an in vitrosystem under the conditions of stable strontium exposure. The children’s population consuming drinking water with high strontium (Sr2+) content (n = 49) was observed. The level of lymphocyte apoptosis was determined with flow cytometry technique, by means of labeled annexin V-FITC conjugate (AnnV-FITC) and propidium iodide (PI) staining. AnnV-FITC+PI- cells were regarded as early apoptotic forms, whereas late apoptotic and/or necrotic cells were AnnV-FITC+PI+. The isolated leukocytes were incubated with Sr2+ at a concentration of 7.0 mg/l, the maximal permitted concentration (MPC) for water of aqueous objects, for 4 hours at 37 ºC. Expression of CD95 and p53 apoptosis markers was performed by flow cytometry using labeled monoclonal antibodies.In vitroexposure to strontium was associated with significantly decreased expression of apoptosisregulating factors, i.e., membrane marker CD95 and intracellular transcription protein p53, 1.56- and 1.68-fold, respectively. Meanwhile, we revealed a significantly (4.68-fold) decreased amounts of AnnV-FITC+PI--cells, as well as a statistically significant (1.35-fold) increase of the AnnV-FITC+PI+-cells. Moreover, the amounts of AnnV-FITC+ PI--lymphocytes in all samples were below the physiological ranges and control values. The number of samples with higher contents of AnnV-FITC+PI+-lymphocyte exceeding the established standards and control values, was 30.8%. Thus, it has been experimentally proven that strontium, at a concentration corresponding to MPC for water objects may significantly inhibit cell death along apoptotic pathways, with switching to necrotic cell death mechanisms, according to phosphatidylserine contents, as detected by annexin V binding test. The data have revealed an ability of strontium to have a significant effect upon the parameters of regulation and maintenance of cellular homeostasis, by influencing the apoptosis intensity, due to shifting a balance towards necrosis and reducing expression of apoptosis-regulating factors. The results of this study may be used in order to identify some marker indexes of immune disorders potentially induced by external influence of strontium upon human health under specific environmental factors.

Download Full-text

Flow Cytometry and FTIR Spectroscopy for Detection of Early Apoptosis in Human T Cells

Proceedings ◽

10.3390/proceedings2251558 ◽

2018 ◽

Vol 2 (25) ◽

pp. 1558 ◽

Cited By ~ 1

Author(s):

Günnur Güler ◽

Ayten Nalbant

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Cell Death ◽

Ftir Spectroscopy ◽

Apoptotic Cell ◽

Annexin V ◽

Apoptotic Cell Death ◽

Biochemical Changes ◽

Human T Cells ◽

Early Apoptosis

Apoptosis, a programmed cell death, has a vital role in various cellular processes. Apoptotic cells exhibit morphological and biochemical changes, detected by a variety of assays (caspases, mitochondrial dyes, DNA laddering). Flow cytometry is a powerful tool for detection of apoptotic cell death and allows information about the cell size and molecules associated with cell-bound antibodies. Recently, Fourier transform infrared (FTIR) spectroscopy as rapid and low-cost tool has been extensively used for cellular studies, providing information on cellular structures. The aim of this study was to detect early apoptosis and obtain further insights into the capability of FTIR spectroscopy, comparing the results with flow cytometry. In this study, apoptotic cell death was induced in human Jurkat T cells with Camptothecin (CPT), a DNA topoisomerase I inhibitor. Cells were cultured with 4µM CPT in RPMI (with 5% FCS) for 24 h. Immunoflourescence labeling for multicolor flow cytometry was accomplished with Annexin V concomitantly with 7-AAD. The same cells were also analyzed with ATR-FTIR spectroscopy. Flow cytometry data represents that the cells are Annexin V positive but 7AAD negative. This indicates that cells are in the early apoptotic stage, only externalization of phosphatidylserine exists on the plasma membrane. FTIR data reveals that membrane phospholipids and proteins undergo changes; fatty acid acyl chains are disordered and increased in mobility after treatment, which result from the early apoptosis process after CPT-treatment, confirmed by the flow cytometry. A combined study of flow cytometry and FTIR spectroscopy for analysis of apoptosis in human T cells exhibited compatible and complementary results. Existence of biophysical and biochemical changes in T cells after treatment were also demonstrated.

Download Full-text

Eosinophil Cell Death Determination: Role for ERK in the Mechanism Regulating Decision Between Eosinophil Activation, Apoptosis or Regulated Necrosis.

Blood ◽

10.1182/blood.v120.21.2134.2134 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2134-2134

Author(s):

Gen Kano ◽

Maha Almanan ◽

Bruce Bochner ◽

Nives Zimmermann

Keyword(s):

Cell Death ◽

Conflicts Of Interest ◽

Membrane Integrity ◽

Annexin V ◽

Ros Production ◽

Survival Factor ◽

Cell Death Pathway ◽

Eosinophil Cell ◽

Regulated Necrosis ◽

Eosinophil Activation

Abstract Abstract 2134 Siglec-8 is a membrane protein predominantly expressed on eosinophils, where its ligation induces cell death. Paradoxically, Siglec-8-induced cell death is markedly enhanced by the eosinophil activation and survival factor IL-5. Thus, Siglec-8 induces cell death preferentially in activated eosinophils, making it an attractive therapeutic target for eosinophil-mediated diseases. However, the mechanism of this survival factor-enhanced cell death is not known. While Siglec-8 ligation (by anti-Siglec-8 antibody) induces caspase-dependent apoptosis in resting eosinophils, it induces caspase-independent cell death in activated eosinophils. We hypothesize that co-stimulating the Siglec-8 and IL-5 pathways induces a necrotic cell death pathway. By morphologically characterizing human peripheral blood eosinophils as “apoptotic” (i.e., shrunk cells with condensed chromatin) or “necrotic” (i.e., swollen cells, disrupted membrane integrity), we found that anti-Siglec-8 + IL-5 co-stimulation yielded more necrotic eosinophils (P = 0.055, 6 donors) than stimulation with anti-Siglec-8 alone. Additionally, we stained with Annexin V and 7AAD and assessed the percent of Annexin V+ cells that are 7AAD+ as an indicator of increased transition of apoptotic cells to secondary necrosis and/or cells dying primarily by necrosis. We found that anti-Siglec-8 + IL-5 co-stimulated cells had a higher ratio of 7AAD+ cells compared with cells treated with anti-Siglec-8 alone (P < 0.001, 25 experiments with 11 independent donors). This higher 7AAD+ ratio, the morphological characteristics and the caspase-independent cell death of co-stimulated cells suggest that Siglec-8 ligation induces a necrotic form of cell death in IL-5-stimulated eosinophils by activating a specific and distinct biochemical pathway. Our previous studies have shown that reactive oxygen species (ROS) production is involved in Siglec-8-induced cell death in both resting and activated eosinophils. However, we have observed that phosphorylation of ERK1/2 and MEK1 was significantly increased in cells co-stimulated with anti-Siglec-8 + IL-5 compared to cells stimulated with IL-5 alone; anti-Siglec-8 alone did not cause ERK1/2 phosphorylation. MEK1 inhibitors U0126 and PD184352 completely blocked anti-Siglec-8 + IL-5-induced cell death; however, intracellular ROS production induced by Siglec-8 ligation was MEK1-independent. In contrast, the ROS inhibitor DPI prevented the anti-Siglec-8 + IL-5-induced enhancement of ERK1/2 phosphorylation and subsequent cell death. Enhanced ROS accumulation in IL-5 treated cells was sufficient to induce enhanced cell death, similar to anti-Siglec-8 treatment. These findings suggest that Siglec-8 ligation leads to ROS-dependent enhancement of IL-5-induced ERK1/2 phosphorylation, which results in enhanced Siglec-8-induced eosinophil cell death. How ERK phosphorylation induces cell death in co-stimulated eosinophils is not known, and ERK's involvement is surprising considering its role in activation of IL-5-stimulated eosinophils. However, recent studies have shown that ERK can be involved in specific types of cell death, namely necroptosis or autophagy, and that spatiotemporal parameters determine whether ERK will induce cell death or activation. Thus, we hypothesized that ERK localization will be altered in eosinophils co-stimulated with anti-Siglec-8 + IL-5 compared with cells treated with IL-5 alone. Western blotting of nuclear and cytoplasmic fractions and immunofluorescence suggest that enhanced ERK1/2 localization and phosphorylation are sustained for at least 2 hours in the nucleus of anti-Siglec-8 + IL-5 co-stimulated cells; cells treated with IL-5 alone have only brief ERK1/2 nuclear localization. The sustained nuclear activation of ERK may explain the change in IL-5 function from eosinophil activation/survival to necrotic death upon Siglec-8 ligation. In summary, ERK is involved in regulating the decision point for eosinophil activation, apoptosis or regulated necrosis. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Critical Evaluation of Techniques to Detect and Measure Cell Death – Study in a Model of UV Radiation of the Leukaemic Cell Line HL60

Analytical Cellular Pathology ◽

10.1155/1999/176515 ◽

1999 ◽

Vol 19 (3-4) ◽

pp. 139-151 ◽

Cited By ~ 108

Author(s):

Marina Leite ◽

Margarida Quinta‐Costa ◽

Pedro Simas Leite ◽

José Eduardo Guimarães

Keyword(s):

Flow Cytometry ◽

Cell Death ◽

Fluorescence Microscopy ◽

Trypan Blue ◽

Critical Evaluation ◽

Annexin V ◽

Tunel Assay ◽

Apoptotic Cells ◽

Dna Ladder ◽

Apoptosis And Necrosis

The reliability of eight distinct methods (Giemsa staining, trypan blue exclusion, acridine orange/ethidium bromide (AO/EB) double staining for fluorescence microscopy and flow cytometry, propidium iodide (PI) staining, annexin V assay, TUNEL assay and DNA ladder) for detection and quantification of cell death (apoptosis and necrosis) was evaluated and compared. Each of these methods detects different morphological or biochemical features of these two processes. The comparative analysis of the 8 techniques revealed that AO/EB (read in fluorescence microscopy) provides a reliable method to measure cells in different compartments (or pathways) of cell death though it is very time consuming. PI staining and TUNEL assay were also sensitive in detecting very early signs of apoptosis, but do not allow precise quantification of apoptotic cells. These three methods were concordant in relation to induction of apoptosis and necrosis in HL60 cells with the various UV irradiation time periods tested. Both AO/EB (read by flow cytometry) and annexin V‐FITC/PI failed to detect the same number of early apoptotic cells as the other three methods. Trypan blue is valueless for this purpose. Giemsa and DNA ladder might be useful as confirmatory tests in some situations.

Download Full-text

Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes

Blood ◽

10.1182/blood-2007-01-071167 ◽

2007 ◽

Vol 110 (12) ◽

pp. 3968-3977 ◽

Cited By ~ 29

Author(s):

Dirk Brenner ◽

Alexander Golks ◽

Mareike Becker ◽

Wolfgang Müller ◽

Christian R. Frey ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Cell Fate ◽

B Lymphocytes ◽

T And B Lymphocytes ◽

Cell Death Pathways ◽

Activation Induced Cell Death ◽

Cell Death Pathway ◽

Dependent Cell ◽

Interfering Rna

Abstract Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-κB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-κB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2–driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C se-lectively blocks induction of NF-κB–dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C–dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.

Download Full-text

Tetrocarcin-A—induced ER stress mediates apoptosis in B-CLL cells via a Bcl-2—independent pathway

Blood ◽

10.1182/blood-2002-08-2501 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4561-4568 ◽

Cited By ~ 38

Author(s):

Gabriele Anether ◽

Inge Tinhofer ◽

Monika Senfter ◽

Richard Greil

Keyword(s):

T Cells ◽

Cell Death ◽

Er Stress ◽

Clinical Stage ◽

Response To Therapy ◽

Lymphocytic Leukemia ◽

Clinical Markers ◽

Expression Levels ◽

Cell Death Pathway

Abstract Tetrocarcin-A (TC-A), an antibiotic agent isolated from actinomycetes, has recently been described to antagonize Bcl-2 functions, thereby sensitizing tumor cells to cell death signals under control of Bcl-2. In this study, we analyzed the direct proapoptotic effect of TC-A in the B-chronic lymphocytic leukemia (B-CLL) model. We focused on the signal cascade triggered by TC-A in B-CLL cells and identified activated mitochondrial as well as endoplasmatic reticulum (ER) stress signals. The expression levels of known effector molecules mediating mitochondrial signaling, such as Bax and Bid, and the antagonistic molecule Bcl-2 did not influence sensitivity of B-CLL cells to TC-A. Furthermore, the molecular chaperone and sensor of ER stress, HSP70, though significantly up-regulated in B-CLL cells undergoing TC-A—triggered apoptosis, was ineffective to exert its anti-apoptotic function described in multiple cell death pathways. Autologous T cells of B-CLL patients were significantly less sensitive to TC-A as were also T cells from healthy donors when compared with their normal B-cell fraction. Furthermore, sensitivity of B-CLL cells to TC-A treatment in vitro was dependent neither on the expression levels of CD38—a prognostic factor for survival of B-CLL patients as well as for their response to therapy—nor on the clinical stage or pretreatment status of patients. From our data showing that TC-A induced a cell death pathway via ER stress preferentially in B cells and that it acted independently of important markers of drug sensitivity and of clinical markers, we conclude that TC-A might represent an attractive candidate drug for further evaluation in preclinical trials.

Download Full-text

Highlighting curcumin-induced crosstalk between autophagy and apoptosis: A biochemical approach coupling impedancemetry, imaging, and flow cytometry

10.1101/827279 ◽

2019 ◽

Author(s):

Francisco José Sala de Oyanguren ◽

Nathan E. Rainey ◽

Aoula Moustapha ◽

Ana Saric ◽

Franck Sureau ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Death ◽

Er Stress ◽

Calcium Release ◽

Curcuma Longa ◽

Cancer Cell Growth ◽

Unfolded Protein ◽

The Status ◽

Type Ii Cell

Curcumin, a major active component of turmeric (Curcuma longa, L.), is known to have various effects on both healthy and cancerous tissues. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying the anticancer effects of curcumin is still unclear. Since there is a consensus about endoplasmic reticulum (ER) stress being involved in the cytotoxicity of many natural compounds, we investigated by Amnis®Imaging flow cytometry the mechanistic aspects of curcumin’s destabilization of the ER, but also the status of the lysosomal compartment involved in curcumin-associated apoptosis. Curcumin induces ER stress thereby causing an unfolded protein response (UPR) and calcium release which destabilize the mitochondrial compartment and induce apoptosis. These events are also associated with secondary lysosomal membrane permeabilization and activation of caspase-8, mediated by activation of cathepsins and calpains. We previously showed that sequence lead to the generation of truncated tBid and disruption of mitochondrial homeostasis. These two pathways of different intensities and momentum converge towards an amplification of cell death that still needs to be studied in more detail. It has been suggested that it may be possible to exploit autophagy for cancer therapy. There is a complex interplay involving early autophagy as soon as mitochondria produce superoxide anions and hydrogen peroxide. Treatments with 10 µM to 20 µM curcumin induce autophagosome formation, while only early events of cell death are detectable.In the present study, curcumin-induced autophagy failed to rescue all cells since most cells underwent type II cell death following initial autophagic processes. However, a small number of cells blocked in the cell cycle escaped and were rescued to give rise to a novel proliferation phase.

Download Full-text

Iron and Cancer

Annual Review of Nutrition ◽

10.1146/annurev-nutr-082117-051732 ◽

2018 ◽

Vol 38 (1) ◽

pp. 97-125 ◽

Cited By ~ 51

Author(s):

Suzy V. Torti ◽

David H. Manz ◽

Bibbin T. Paul ◽

Nicole Blanchette-Farra ◽

Frank M. Torti

Keyword(s):

Cell Death ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Biology ◽

Experimental Studies ◽

Epidemiological Studies ◽

Excess Iron ◽

Cell Death Pathways ◽

Dependent Form ◽

Active Research

This review explores the multifaceted role that iron has in cancer biology. Epidemiological studies have demonstrated an association between excess iron and increased cancer incidence and risk, while experimental studies have implicated iron in cancer initiation, tumor growth, and metastasis. The roles of iron in proliferation, metabolism, and metastasis underpin the association of iron with tumor growth and progression. Cancer cells exhibit an iron-seeking phenotype achieved through dysregulation of iron metabolic proteins. These changes are mediated, at least in part, by oncogenes and tumor suppressors. The dependence of cancer cells on iron has implications in a number of cell death pathways, including ferroptosis, an iron-dependent form of cell death. Uniquely, both iron excess and iron depletion can be utilized in anticancer therapies. Investigating the efficacy of these therapeutic approaches is an area of active research that promises substantial clinical impact.

Download Full-text