Analytic Considerations and Axiomatic Approaches to the Concept Cell Death and Cell Survival Functions in Biology and Cancer Treatment

: During cancer progression, the unrestricted proliferation of cells is supported by the impaired cell death response provoked by certain oncogenes. Both autophagy and apoptosis are the signaling pathways of cell death, which are targeted for cancer treatment. Defects in apoptosis result in reduced cell death and ultimately tumor progression. The tumor cells lacking apoptosis phenomena are killed by ROS- mediated autophagy. The autophagic programmed cell death requires apoptosis protein for inhibiting tumor growth; thus, the interconnection between these two pathways determines the fate of a cell. The cross-regulation of autophagy and apoptosis is an important aspect to modulate autophagy, apoptosis and to sensibilise apoptosis-resistant tumor cells under metabolic stress and might be a rational approach for drug designing strategy for the treatment of cancer. Numerous proteins involved in autophagy have been investigated as the druggable target for anticancer therapy. Several compounds of natural origin have been reported, to control autophagy activity through the PI3K/Akt/mTOR key pathway. Diosgenin, a steroidal sapogenin has emerged as a potential candidate for cancer treatment. It induces ROS-mediated autophagy, inhibits PI3K/Akt/mTOR pathway, and produces cytotoxicity selectively in cancer cells. This review aims to focus on optimal strategies using diosgenin to induce apoptosis by modulating the pathways involved in autophagy regulation and its potential implication in the treatment of various cancer. The discussion has been extended to the medicinal chemistry of semi-synthetic derivatives of diosgenin exhibiting anticancer activity.

Download Full-text

Neuroglobin and Estrogen Receptors: A New Pathway of Cell Survival and Cell Death Balance

Immunology Endocrine & Metabolic Agents - Medicinal Chemistry ◽

10.2174/1871522214666141014230636 ◽

2015 ◽

Vol 14 (2) ◽

pp. 91-99 ◽

Cited By ~ 2

Author(s):

Maria T. Nuzzo ◽

Marco Fiocchetti ◽

Paolo Ascenzi ◽

Maria Marino

Keyword(s):

Cell Death ◽

Estrogen Receptors ◽

Cell Survival

Download Full-text

LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽

10.1038/s41389-021-00306-1 ◽

2021 ◽

Vol 10 (2) ◽

Author(s):

Yu Geon Lee ◽

Hui Won Kim ◽

Yeji Nam ◽

Kyeong Jin Shin ◽

Yu Jin Lee ◽

...

Keyword(s):

Cell Death ◽

Cell Growth ◽

Cell Survival ◽

Cancer Cell ◽

Stress Responses ◽

Molecular Mechanisms ◽

Tca Cycle ◽

Mitochondrial Matrix ◽

Mitochondrial Functions ◽

Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

Download Full-text

A Screen for Mutations That Suppress the Phenotype of Drosophila armadillo, the β-Catenin Homolog

Genetics ◽

10.1093/genetics/155.4.1725 ◽

2000 ◽

Vol 155 (4) ◽

pp. 1725-1740

Author(s):

Rachel T Cox ◽

Donald G McEwen ◽

Denise L Myster ◽

Robert J Duronio ◽

Joseph Loureiro ◽

...

Keyword(s):

Cell Death ◽

Cell Adhesion ◽

Programmed Cell Death ◽

Cell Survival ◽

Wnt Pathway ◽

Genetic Modifier ◽

Wnt Signaling Pathway ◽

Adherens Junction ◽

Cell Fates ◽

Wnt Signal

Abstract During development signaling pathways coordinate cell fates and regulate the choice between cell survival or programmed cell death. The well-conserved Wingless/Wnt pathway is required for many developmental decisions in all animals. One transducer of the Wingless/Wnt signal is Armadillo/β-catenin. Drosophila Armadillo not only transduces Wingless signal, but also acts in cell-cell adhesion via its role in the epithelial adherens junction. While many components of both the Wingless/Wnt signaling pathway and adherens junctions are known, both processes are complex, suggesting that unknown components influence signaling and junctions. We carried out a genetic modifier screen to identify some of these components by screening for mutations that can suppress the armadillo mutant phenotype. We identified 12 regions of the genome that have this property. From these regions and from additional candidate genes tested we identified four genes that suppress arm: dTCF, puckered, head involution defective (hid), and Dpresenilin. We further investigated the interaction with hid, a known regulator of programmed cell death. Our data suggest that Wg signaling modulates Hid activity and that Hid regulates programmed cell death in a dose-sensitive fashion.

Download Full-text

Steroid Hormone Control of Cell Death and Cell Survival: Molecular Insights Using RNAi

PLoS Genetics ◽

10.1371/journal.pgen.1000379 ◽

2009 ◽

Vol 5 (2) ◽

pp. e1000379 ◽

Cited By ~ 17

Author(s):

Suganthi Chittaranjan ◽

Melissa McConechy ◽

Ying-Chen Claire Hou ◽

J. Douglas Freeman ◽

Lindsay DeVorkin ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Steroid Hormone ◽

Hormone Control

Download Full-text

Pancreatic islet cell survival following islet isolation: the role of cellular interactions in the pancreas

Journal of Endocrinology ◽

10.1677/joe.0.1610357 ◽

1999 ◽

Vol 161 (3) ◽

pp. 357-364 ◽

Cited By ~ 102

Author(s):

A Ilieva ◽

S Yuan ◽

RN Wang ◽

D Agapitos ◽

DJ Hill ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Islet Cell ◽

Apoptotic Cell ◽

Specific Cell ◽

Cellular Interactions ◽

Pancreatic Islet Cell ◽

Beneficial Result ◽

Trophic Effect ◽

Ductal Epithelium

The purpose of this study was to characterize the trophic effect of pancreatic duct cells on the islets of Langerhans. Ductal epithelium and islets were isolated from hamster pancreata. In addition, duct-conditioned medium (DCM) was prepared from primary duct cultures that had been passaged twice to remove other cellular elements. Three experimental groups were then established: Group 1, 100 islets alone; Group 2, 100 islets+80 duct fragments; and Group 3, 100 islets in 25% DCM. All tissues were embedded in rat tail collagen for up to 12 days and the influence of pancreatic ductal epithelium on islet cell survival was examined. By day 12, 20.6+/-3. 0% (S.E.M.) of the islets cultured alone developed central necrosis, compared with 6.7+/-2.0% of the islets co-cultured with ducts and 5.6+/-1.5% of the islets cultured in DCM (P<0.05). The presence of apoptotic cell death was determined by a TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and by a specific cell death ELISA. DNA fragmentation in islets cultured alone was significantly increased compared with islets cultured either in the presence of duct epithelium or in DCM (P<0.05). More than 80% of TUNEL-positive cells were situated in the inner 80% of the islet area, suggesting that most were beta-cells. DCM was analysed for known growth factors. The presence of a large amount of IGF-II (34 ng/ml) and a much smaller quantity of nerve growth factor (4 ng/ml) was identified. When the apoptosis studies were repeated to compare islets alone, islets+DCM and islets+IGF-II, the cell death ELISA indicated that IGF-II produced the same beneficial result as DCM when compared with islets cultured alone. We conclude that pancreatic ductal epithelium promotes islet cell survival. This effect appears to be mediated in a paracrine manner by the release of IGF-II from cells in the ductal epithelium.

Download Full-text

The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia

International Journal of Cancer ◽

10.1002/ijc.21547 ◽

2006 ◽

Vol 118 (7) ◽

pp. 1660-1669 ◽

Cited By ~ 68

Author(s):

Teralee R. Burton ◽

Elizabeth S. Henson ◽

Priti Baijal ◽

David D. Eisenstat ◽

Spencer B. Gibson

Keyword(s):

Cell Death ◽

Glioblastoma Multiforme ◽

Tumor Cell ◽

Cell Survival ◽

Family Member ◽

Glial Cells ◽

Tumor Cell Survival

Download Full-text

Kinase cascades regulating entry into apoptosis

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.61.1.33-46.1997 ◽

1997 ◽

Vol 61 (1) ◽

pp. 33-46

Author(s):

P Anderson

Keyword(s):

Cell Death ◽

Cell Surface ◽

Cell Survival ◽

Tyrosine Kinases ◽

Uv Light ◽

Apoptotic Cell ◽

Paracrine Factors ◽

Surface Receptors ◽

Promote Cell Survival ◽

Necrosis Factor

All cells are constantly exposed to conflicting environment cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. In addition to survival factor withdrawal, cell death can be triggered by environmental stresses such as heat, UV light, and hyperosmolarity or by dedicated death receptors (e.g., FAS/APO-1 and tumor necrosis factor [TNF] receptors) that are counterparts of growth factor or survival receptors at the cell surface. One of the ways that cells integrate conflicting exogenous stimuli is by phosphorylation (or dephosphorylation) of cellular constituents by interacting cascades of serine/threonine and tyrosine protein kinases (and phosphatases). Survival factors (e.g., growth factors and mitogens) activate receptor tyrosine kinases and selected mitogen-activated, cyclin-dependent, lipid-activated, nucleic acid-dependent, and cyclic AMP-dependent kinases to promote cell survival and proliferation, whereas environmental stress (or death factors such as FAS/APO-1 ligand and TNF-alpha) activates different members of these kinase families to inhibit cell growth and, under some circumstances, promote apoptotic cell death. Because individual kinase cascades can interact with one another, they are able to integrate conflicting exogenous stimuli and provide a link between cell surface receptors and the biochemical pathways leading to cell proliferation or cell death.

Download Full-text

Abstract 143: A Novel TAK1 Signaling Network Regulating Programmed Necrosis and Myocardial Remodeling

Circulation Research ◽

10.1161/res.113.suppl_1.a143 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Qinghang Liu ◽

Lei Li ◽

Yi Chen ◽

Jessica Doan ◽

Jeffery Molkentin

Keyword(s):

Heart Failure ◽

Cell Death ◽

Cell Survival ◽

Cardiac Fibrosis ◽

Signaling Network ◽

Specific Gene ◽

Caspase 8 ◽

Programmed Necrosis ◽

Genetic Ablation ◽

Cell Death Pathway

We recently identified a novel signaling molecule, TAK1 (TGFβ-activated kinase 1, also known as MAP3K7), as a key regulator of the hypertrophic signaling network. Importantly, TAK1 is activated in mouse models of heart failure as well as in diseased human myocardium. Here, we defined a previously unidentified, novel role for TAK1 in promoting cardiac cell survival and homeostasis using cardiac-specific gene-targeted mice. Indeed, cardiac-specific ablation of TAK1 in mice using a Cre-LoxP system showed enhanced pathological cardiac remodeling and massive cell death, and these mice gradually developed heart failure and spontaneous death. Remarkably, ablation of TNF receptor 1 (TNFR1) largely rescued the pathological phenotype of TAK1-deficient mice, preventing early lethality and cardiac fibrosis, suggesting that TNFR1 signaling is critical in mediating adverse remodeling and heart failure associated with TAK1 deficiency. Genetic or pharmacological inactivation of TAK1 in cardiomyocytes markedly induced programmed necrosis and apoptosis in response to TNFα. Conversely, overexpression of the constitutively active TAK1 mutant, or TAK1 plus its activator TAB1, protected cardiomyocytes from TNFα-induced cell death. Mechanistically, inactivation of TAK1 promoted formation of the necroptotic cell death complex consisting of RIP1, RIP3, caspase 8, and FADD. Genetic ablation of RIP1, RIP3, caspase 8, or FADD largely blocked TNFα-induced cell death in TAK1-deficient cells, whereas deletion of Bax/Bak or cyclophilin D showed no effects. Further, IKK/NFκB-mediated cell survival signaling was greatly impaired in TAK1-deficient cardiomyocytes. Taken together, our data indicate that TAK1 functions as a critical “molecular switch” in TNFα-induced programmed necrosis in cardiomyocytes, by interacting with the RIP1/3-caspase 8-FADD cell death pathway as well as the IKK-NFκB cell survival pathway. These findings thus define an important TAK1-mediated cardio-protective signaling network in the heart, which may suggest new therapeutic strategies in the treatment of heart disease.

Download Full-text