Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

ABSTRACTPrior studies have found that HIV, through the Vpr protein, promotes genome reduplication (polyploidy) in infection-surviving epithelial cells within renal tissue. However, the temporal progression and molecular regulation through which Vpr promotes polyploidy have remained unclear. Here we define a sequential progression to Vpr-mediated polyploidy in human renal tubule epithelial cells (RTECs). We found that as in many cell types, Vpr first initiates G2cell cycle arrest in RTECs. We then identified a previously unreported cascade of Vpr-dependent events that lead to renal cell survival and polyploidy. Specifically, we found that a fraction of G2-arrested RTECs reenter the cell cycle. Following this cell cycle reentry, two distinct outcomes occur. Cells that enter complete mitosis undergo mitotic cell death due to extra centrosomes and aberrant division. Conversely, cells that abort mitosis undergo endoreplication to become polyploid. We further show that multiple small-molecule inhibitors of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, including those that target ATR, ATM, and mTOR, indirectly prevent Vpr-mediated polyploidy by preventing G2arrest. In contrast, an inhibitor that targets DNA-dependent protein kinase (DNA-PK) specifically blocks the Vpr-mediated transition from G2arrest to polyploidy. These findings outline a temporal, molecularly regulated path to polyploidy in HIV-positive renal cells.IMPORTANCECurrent cure-focused efforts in HIV research aim to elucidate the mechanisms of long-term persistence of HIV in compartments. The kidney is recognized as one such compartment, since viral DNA and mRNA persist in the renal tissues of HIV-positive patients. Further, renal disease is a long-term comorbidity in the setting of HIV. Thus, understanding the regulation and impact of HIV infection on renal cell biology will provide important insights into this unique HIV compartment. Our work identifies mechanisms that distinguish between HIV-positive cell survival and death in a known HIV compartment, as well as pharmacological agents that alter these outcomes.

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Zinc Deficiency Induced Cell Death as a Consequence of Cell Cycle Inhibition and Inactivation of Cell Survival Pathways

The FASEB Journal ◽

10.1096/fasebj.20.5.a996 ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

Brad J. Niles ◽

Lynn A. Hanna ◽

Tony Y. Momma ◽

Michael S. Clegg ◽

Carl L. Keen

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Survival ◽

Zinc Deficiency ◽

Survival Pathways ◽

Cell Cycle Inhibition

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Strategically targeting MYC in cancer

F1000Research ◽

10.12688/f1000research.7879.1 ◽

2016 ◽

Vol 5 ◽

pp. 408 ◽

Cited By ~ 48

Author(s):

Valeriya Posternak ◽

Michael D. Cole

Keyword(s):

Cell Cycle ◽

Cell Growth ◽

Cancer Therapy ◽

Cell Survival ◽

Transcriptional Program ◽

Pharmacokinetics And Pharmacodynamics ◽

Cancer Cell Growth ◽

Therapeutic Value ◽

Direct Inhibitors

MYC is a major driver of cancer cell growth and mediates a transcriptional program spanning cell growth, the cell cycle, metabolism, and cell survival. Many efforts have been made to deliberately target MYC for cancer therapy. A variety of compounds have been generated to inhibit MYC function or stability, either directly or indirectly. The most direct inhibitors target the interaction between MYC and MAX, which is required for DNA binding. Unfortunately, these compounds do not have the desired pharmacokinetics and pharmacodynamics for in vivo application. Recent studies report the indirect inhibition of MYC through the development of two compounds, JQ1 and THZ1, which target factors involved in unique stages of transcription. These compounds appear to have significant therapeutic value for cancers with high levels of MYC, although some effects are MYC-independent. These approaches serve as a foundation for developing novel compounds to pharmacologically target MYC-driven cancers.

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Distinct Signaling Pathways Mediate Stimulation of Cell Cycle Progression and Prevention of Apoptotic Cell Death by Estrogen in Rat Pituitary Tumor PR1 Cells

Molecular Biology of the Cell ◽

10.1091/mbc.e03-05-0303 ◽

2003 ◽

Vol 14 (12) ◽

pp. 5051-5059 ◽

Cited By ~ 12

Author(s):

Simona Caporali ◽

Manami Imai ◽

Lucia Altucci ◽

Massimo Cancemi ◽

Silvana Caristi ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Cell Death ◽

Dna Synthesis ◽

Cell Survival ◽

Pituitary Tumor ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Rat Pituitary ◽

Stimulation Of

Estrogens control cell growth and viability in target cells via an interplay of genomic and extragenomic pathways not yet elucidated. Here, we show evidence that cell proliferation and survival are differentially regulated by estrogen in rat pituitary tumor PR1 cells. Pico- to femtomolar concentrations of 17β-estradiol (E2) are sufficient to foster PR1 cell proliferation, whereas nanomolar concentrations of the same are needed to prevent cell death that occurs at a high rate in these cells in the absence of hormone. Activation of endogenous (PRL) or transfected estrogen-responsive genes occurs at the same, higher concentrations of E2 required to promote cell survival, whereas stimulation of cyclin D3 expression and DNA synthesis occur at lower E2 concentrations. Similarly, the pure antiestrogen ICI 182,780 inhibits estrogen response element-dependent trans-activation and cell death more effectively than cyclin-cdk activity, G1-S transition, or DNA synthesis rate. In antiestrogen-treated and/or estrogen-deprived cells, death is due predominantly to apoptosis. Estrogen-induced cell survival, but not E2-dependent cell cycle progression, can be prevented by an inhibitor of c-Src kinase or by blockade of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathway. These data indicate the coexistence of two distinguishable estrogen signaling pathways in PR1 cells, characterized by different functions and sensitivity to hormones and antihormones.

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Role of DNA Damage and MMP Loss in Radiosensitization-Induced Apoptosis by Ellagic Acid in HeLa Cells

10.21926/obm.genet.2102129 ◽

2020 ◽

Vol 25775790 ◽

pp. 1-1

Author(s):

Vidhula R Ahire ◽

◽

Amit Kumar ◽

Sushma Bhosle ◽

Kaushala Prasad Mishra ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Survival ◽

Hela Cells ◽

Ellagic Acid ◽

Mitochondrial Membrane ◽

Radiation Treatment ◽

Γ Radiation ◽

Anti Cancer

Ellagic acid (EA) is a polyphenol found in grapes, pomegranates, walnuts, etc. exhibits anti-cancer properties. The current study was conducted to understand the radiosensitizing role of EA on HeLa cells. Monotherapy of EA and radiation was initially studied on HeLa cells. The addition of EA before the radiation treatment subsequently made DNA more susceptible to damage thereby developing DNA beaks, which are known to be lethal for cell survival. This was evaluated by performing comet and γ-foci formation assay. Other assays which included cell-cycle distribution, clonogenic cell survival assay, mitochondrial membrane drop, and apoptosis were performed to evaluate the effect of EA with radiation. Our results demonstrate that, when cells were exposed to the combinatorial treatment of EA (10µM) and 2Gy of γ-radiation there was augmented cell death, lesser cell-proliferation, reduction in the colony-forming ability, increased DNA tail length, more number of γ-foci persisting even after 24h, enhanced apoptosis, augmented drop in the mitochondrial membrane potential and a G1 cell-cycle arrest. These results suggest that EA exhibits not only anti-cancer properties in terms of cell-death but also exhibits a radiosensitizing effect when given in combination with γ-radiation. Thus, it can be concluded that EA not only exhibits anticancer effects but also has potential in radiosensitizing HeLa cells.

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Flavin Oxidase-Induced ROS Generation Modulates PKC Biphasic Effect of Resveratrol on Endothelial Cell Survival

Biomolecules ◽

10.3390/biom9060209 ◽

2019 ◽

Vol 9 (6) ◽

pp. 209 ◽

Cited By ~ 14

Author(s):

Anna Maria Posadino ◽

Roberta Giordo ◽

Annalisa Cossu ◽

Gheyath K. Nasrallah ◽

Abdullah Shaito ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Dna Synthesis ◽

Cell Survival ◽

Cellular Response ◽

Cell Cycle Progression ◽

Natural Antioxidants ◽

Cycle Progression ◽

Protein Levels ◽

The Impact

Background: Dietary intake of natural antioxidants is thought to impart protection against oxidative-associated cardiovascular diseases. Despite many in vivo studies and clinical trials, this issue has not been conclusively resolved. Resveratrol (RES) is one of the most extensively studied dietary polyphenolic antioxidants. Paradoxically, we have previously demonstrated that high RES concentrations exert a pro-oxidant effect eventually elevating ROS levels leading to cell death. Here, we further elucidate the molecular determinants underpinning RES-induced oxidative cell death. Methods: Using human umbilical vein endothelial cells (HUVECs), the effect of increasing concentrations of RES on DNA synthesis and apoptosis was studied. In addition, mRNA and protein levels of cell survival or apoptosis genes, as well as protein kinase C (PKC) activity were determined. Results: While high concentrations of RES reduce PKC activity, inhibit DNA synthesis and induce apoptosis, low RES concentrations elicit an opposite effect. This biphasic concentration-dependent effect (BCDE) of RES on PKC activity is mirrored at the molecular level. Indeed, high RES concentrations upregulate the proapoptotic Bax, while downregulating the antiapoptotic Bcl-2, at both mRNA and protein levels. Similarly, high RES concentrations downregulate the cell cycle progression genes, c-myc, ornithine decarboxylase (ODC) and cyclin D1 protein levels, while low RES concentrations display an increasing trend. The BCDE of RES on PKC activity is abrogated by the ROS scavenger Tempol, indicating that this enzyme acts downstream of the RES-elicited ROS signaling. The RES-induced BCDE on HUVEC cell cycle machinery was also blunted by the flavin inhibitor diphenyleneiodonium (DPI), implicating flavin oxidase-generated ROS as the mechanistic link in the cellular response to different RES concentrations. Finally, PKC inhibition abrogates the BCDE elicited by RES on both cell cycle progression and pro-apoptotic gene expression in HUVECs, mechanistically implicating PKC in the cellular response to different RES concentrations. Conclusions: Our results provide new molecular insight into the impact of RES on endothelial function/dysfunction, further confirming that obtaining an optimal benefit of RES is concentration-dependent. Importantly, the BCDE of RES could explain why other studies failed to establish the cardio-protective effects mediated by natural antioxidants, thus providing a guide for future investigation looking at cardio-protection by natural antioxidants.

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Cell-cycle arrest versus cell death in cancer therapy

Nature Medicine ◽

10.1038/nm0997-1034 ◽

1997 ◽

Vol 3 (9) ◽

pp. 1034-1036 ◽

Cited By ~ 231

Author(s):

Todd Waldman ◽

Yonggang Zhang ◽

Larry Dillehay ◽

Jian Yu ◽

Kenneth Kinzler ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cancer Therapy ◽

Cell Cycle Arrest ◽

Cycle Arrest

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Faculty Opinions recommendation of Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1007206.89506 ◽

2002 ◽

Author(s):

Antony Carr

Keyword(s):

Cell Cycle ◽

Cell Death

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New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

Current Medicinal Chemistry ◽

10.2174/0929867324666170830094922 ◽

2018 ◽

Vol 25 (36) ◽

pp. 4758-4784 ◽

Cited By ~ 8

Author(s):

Amy L. Wilson ◽

Magdalena Plebanski ◽

Andrew N. Stephens

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Immune System ◽

Cancer Therapy ◽

Immune Cell ◽

Cytotoxic T Lymphocyte ◽

Tumour Microenvironment ◽

Immune Checkpoints ◽

Tumour Regression ◽

Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

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