scholarly journals RAB38 Facilitates Energy Metabolism and Counteracts Cell Death in Glioblastoma Cells

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1643
Author(s):  
Elena Bianchetti ◽  
Sierra J. Bates ◽  
Trang T. T. Nguyen ◽  
Markus D. Siegelin ◽  
Kevin A. Roth
Keyword(s):  
Cell Death ◽  
Patient Survival ◽  
Intrinsic Apoptosis ◽  
Potential Therapeutic Target ◽  
Rapid Reduction ◽  
Inhibition Of Proliferation ◽  
Protein Levels ◽  
Genetic Interference ◽  
Glioblastoma Cell Lines

Glioblastoma is a high-grade glial neoplasm with a patient survival of 12–18 months. Therefore, the identification of novel therapeutic targets is an urgent need. RAB38 is a GTPase protein implicated in regulating cell proliferation and survival in tumors. The role of RAB38 in glioblastoma is relatively unexplored. Here, we test the hypothesis that RAB38 regulates glioblastoma growth using human glioblastoma cell lines. We found that genetic interference of RAB38 resulted in a decrease in glioblastoma growth through inhibition of proliferation and cell death induction. Transcriptome analysis showed that RAB38 silencing leads to changes in genes related to mitochondrial metabolism and intrinsic apoptosis (e.g., Bcl-xL). Consistently, rescue experiments demonstrated that loss of RAB38 causes a reduction in glioblastoma viability through downregulation of Bcl-xL. Moreover, RAB38 knockdown inhibited both glycolysis and oxidative phosphorylation. Interference with RAB38 enhanced cell death induced by BH3-mimetics. RAB38 antagonists are under development, but not yet clinically available. We found that FDA-approved statins caused a rapid reduction in RAB38 protein levels, increased cell death, and phenocopied some of the molecular changes elicited by loss of RAB38. In summary, our findings suggest that RAB38 is a potential therapeutic target for glioblastoma treatment.

scholarly journals YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Lan Jin ◽  
Yunhe Chen ◽  
Dan Cheng ◽  
Zhikai He ◽  
Xinyi Shi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Transcriptional Coactivator ◽  
Inhibitory Protein ◽  
Potential Therapeutic Target ◽  
Related Cell ◽  
Autophagy Inhibition

AbstractColorectal cancer (CRC) is one of the most aggressive and lethal cancers. The role of autophagy in the pathobiology of CRC is intricate, with opposing functions manifested in different cellular contexts. The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor-suppressor pathway, functions as an oncoprotein in a variety of cancers. In this study, we found that YAP could negatively regulate autophagy in CRC cells, and consequently, promote tumor progression of CRC in vitro and in vivo. Mechanistically, YAP interacts with TEAD forming a complex to upregulate the transcription of the apoptosis-inhibitory protein Bcl-2, which may subsequently facilitate cell survival by suppressing autophagy-related cell death; silencing Bcl-2 expression could alleviate YAP-induced autophagy inhibition without affecting YAP expression. Collectively, our data provide evidence for YAP/Bcl-2 as a potential therapeutic target for drug exploration against CRC.

scholarly journals Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 587 ◽  
Author(s):  
Matilda Munksgaard Thorén ◽  
Katarzyna Chmielarska Masoumi ◽  
Cecilia Krona ◽  
Xiaoli Huang ◽  
Soumi Kundu ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Target ◽  
Functional Role ◽  
Treatment Strategies ◽  
Antibody Drug Conjugate ◽  
Potential Therapeutic Target ◽  
Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

scholarly journals Bcl2 inhibits apoptosis associated with terminal differentiation of HL- 60 myeloid leukemia cells

Blood ◽  
1994 ◽  
Vol 83 (8) ◽  
pp. 2261-2267 ◽  
Author(s):  
L Naumovski ◽  
ML Cleary
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Myeloid Cells ◽  
Terminal Differentiation ◽  
Retroviral Gene Transfer ◽  
Protein Levels ◽  
All Trans Retinoic Acid ◽  
Bcl2 Protein ◽  
The Relationship

Abstract The Bcl2 protein inhibits apoptosis (programmed cell death) induced by a variety of noxious stimuli. However, relatively little is known about its effect on apoptosis that occurs after terminal differentiation. Bcl2 protein levels decrease during differentiation of myeloid cells into granulocytes that subsequently undergo apoptosis, but the potential role of Bcl2 in coupling survival and differentiation remains undefined. To ascertain the relationship between decreasing Bcl2 levels and the onset of apoptosis in differentiating myeloid cells, Bcl2 was hyperexpressed in the HL-60 cell line after retroviral gene transfer. After treatment of HL-60/BCL2 cells with all-trans retinoic acid or phorbol myristic acid, Bcl2 levels did not decrease as in normal HL-60 cells but, rather, increased because of activation of the viral promoter. Differentiation of the Bcl2-overexpressing cells was similar to that of normal HL-60 cells, but they showed little evidence for apoptosis and had a prolonged survival. These studies show that the survival-enhancing properties of Bcl2 counteract programmed cell death that accompanies terminal differentiation; however, Bcl2 has no significant effect on differentiation itself, suggesting that apoptosis and differentiation are regulated independently in myeloid cells.

scholarly journals A20 Promotes Ripoptosome Formation and TNF-Induced Apoptosis via cIAPs Regulation and NIK Stabilization in Keratinocytes

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 351 ◽  
Author(s):  
Maria Feoktistova ◽  
Roman Makarov ◽  
Sihem Brenji ◽  
Anne T. Schneider ◽  
Guido J. Hooiveld ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Skin Diseases ◽  
Signaling Mechanism ◽  
Protein Levels ◽  
Genome Wide ◽  
Multiple Levels ◽  
Subsequent Activation ◽  
Induced Apoptosis

The ubiquitin-editing protein A20 (TNFAIP3) is a known key player in the regulation of immune responses in many organs. Genome-wide associated studies (GWASs) have linked A20 with a number of inflammatory and autoimmune disorders, including psoriasis. Here, we identified a previously unrecognized role of A20 as a pro-apoptotic factor in TNF-induced cell death in keratinocytes. This function of A20 is mediated via the NF-κB-dependent alteration of cIAP1/2 expression. The changes in cIAP1/2 protein levels promote NIK stabilization and subsequent activation of noncanonical NF-κB signaling. Upregulation of TRAF1 expression triggered by the noncanonical NF-κB signaling further enhances the NIK stabilization in an autocrine manner. Finally, stabilized NIK promotes the formation of the ripoptosome and the execution of cell death. Thus, our data demonstrate that A20 controls the execution of TNF-induced cell death on multiple levels in keratinocytes. This signaling mechanism might have important implications for the development of new therapeutic strategies for the treatment of A20-associated skin diseases.

scholarly journals Detrimental and Beneficial Effect of Autophagy and a Potential Therapeutic Target after Ischemic Stroke

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Meng Wang ◽  
Hangil Lee ◽  
Kenneth Elkin ◽  
Redina Bardhi ◽  
Longfei Guan ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Therapeutic Target ◽  
Ischemic Injury ◽  
Potential Therapeutic Target ◽  
Physiologic Mechanism ◽  
Promote Cell Survival ◽  
Cellular Components ◽  
Neuroprotective Therapies

Autophagy, a physiologic mechanism that promotes energy recycling and orderly degradation through self-regulated disassembly of cellular components, helps maintain homeostasis. A series of evidences suggest that autophagy is activated as a response to ischemia and has been well-characterized as a therapeutic target. However, the role of autophagy after ischemia remains controversial. Activated-autophagy can remove necrotic substances against ischemic injury to promote cell survival. On the contrary, activation of autophagy may further aggravate ischemic injury, causing cell death. Therefore, the present review will examine the current understanding of the precise mechanism and role of autophagy in ischemia and recent neuroprotective therapies on autophagy, drug therapies, and nondrug therapies, including electroacupuncture (EA).

Abstract 25: The Role of cAMP-Phosphodiesterase 1C Signaling in Pathological Cardiac Remodeling and Dysfunction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Walter E Knight ◽  
Masayoshi Oikawa ◽  
Clint Miller ◽  
Chen Yan
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Specific Effect ◽  
Cardiomyocyte Hypertrophy ◽  
Protective Mechanism ◽  
Ang Ii ◽  
Camp Phosphodiesterase ◽  
Protein Levels ◽  
Camp And Cgmp

The cyclic nucleotides cAMP and cGMP play important roles in mediating both protective and detrimental signaling in heart failure. By acting as regulators of cAMP and cGMP, the phosphodiesterases play important roles in modulating this signaling. A comparison of PDE expression between control mice and mice given transverse aortic constriction revealed that expression of phosphodiesterase 1C (PDE1C) was increased significantly by TAC, both on the mRNA and protein levels. To determine whether this was protective or maladaptive, we performed TAC on mice with a genetic deletion of PDE1C. While TAC-operated WT mice experienced significant overall cardiac hypertrophy and cardiomyocyte hypertrophy, these were reduced in PDE1C KO mice. Cardiac function, as assessed by echocardiography, was also reduced significantly in WT TAC mice, but was preserved in PDE1C KO TAC mice. Histological analysis indicated that TAC-operated PDE1C KO mice also experienced reduced cardiomyocyte apoptosis compared to WT mice, indicating a potential cardioprotective mechanism for PDE1C deletion. Cardiomyocytes isolated from PDE1C KO mice experienced reduced Ang II or Iso-induced cell death compared to WT myocytes, indicating that this was a cardiomyocytes-specific effect of PDE1C deletion. Ang II-induced cardiomyocyte cell death and apoptosis were also blocked via pharmacological PDE1 inhibition. PDE1C is able to hydrolyze either cAMP or cGMP; therefore, it seemed possible that this protective mechanism was dependent on either PKA- or PKG-mediated signaling. While PKG inhibition did not alter the protective effect of PDE1 inhibition in isolated cardiomyocytes, PKA inhibition blocked it. Overexpression studies also indicated that PDE1C is localized to the cell membrane in cardiomyocytes. Therefore, we propose that by modulating a novel, membrane-localized, anti-apoptotic, cAMP/PKA-dependent pathway in cardiomyocytes, PDE1C potentially represents a novel therapeutic target in heart failure.

scholarly journals Underlying mechanisms of glucocorticoid-induced β-cell death and dysfunction: a new role for glycogen synthase kinase 3

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Etienne Delangre ◽  
Junjun Liu ◽  
Stefania Tolu ◽  
Kamel Maouche ◽  
Mathieu Armanet ◽  
...  
Keyword(s):  
Cell Death ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Β Cells ◽  
Β Cell ◽  
Protein Levels ◽  
Underlying Mechanisms ◽  
Apoptotic Effects

AbstractGlucocorticoids (GCs) are widely prescribed for their anti-inflammatory and immunosuppressive properties as a treatment for a variety of diseases. The use of GCs is associated with important side effects, including diabetogenic effects. However, the underlying mechanisms of GC-mediated diabetogenic effects in β-cells are not well understood. In this study we investigated the role of glycogen synthase kinase 3 (GSK3) in the mediation of β-cell death and dysfunction induced by GCs. Using genetic and pharmacological approaches we showed that GSK3 is involved in GC-induced β-cell death and impaired insulin secretion. Further, we unraveled the underlying mechanisms of GC-GSK3 crosstalk. We showed that GSK3 is marginally implicated in the nuclear localization of GC receptor (GR) upon ligand binding. Furthermore, we showed that GSK3 regulates the expression of GR at mRNA and protein levels. Finally, we dissected the proper contribution of each GSK3 isoform and showed that GSK3β isoform is sufficient to mediate the pro-apoptotic effects of GCs in β-cells. Collectively, in this work we identified GSK3 as a viable target to mitigate GC deleterious effects in pancreatic β-cells.

scholarly journals Oxidative stress induces cell death partially by decreasing both mRNA and protein levels of nicotinamide phosphoribosyltransferase in PC12 cells

2020 ◽  
Author(s):  
Cuiyan Zhou ◽  
Weihai Ying
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Pc12 Cells ◽  
Mrna Levels ◽  
Salvage Pathway ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Protein Levels ◽  
Pathological Conditions ◽  
Important Enzyme

AbstractNumerous studies have indicated critical roles of NAD+ deficiency in both aging and multiple major diseases. It is critical to investigate the mechanisms underlying the NAD+ deficiency under the pathological conditions. It has been reported that there was a decreased level of Nicotinamide phosphoribosyltransferase (Nampt) – an important enzyme in the salvage pathway of NAD+ synthesis – under certain pathological conditions, while the mechanisms underlying the Nampt decrease require investigation. In this study we used differentiated PC12 cells as a cellular model to investigate the effects of oxidative stress on both the mRNA and protein levels of Nampt, as well as the role of this effect in oxidative stress-induced cell death: First, Nampt plays significant roles in both the NAD+ synthesis and survival of the cells under basal conditions; second, H2O2 produced significant decreases in both the mRNA levels and the protein levels of Nampt; and third, H2O2 induced cell death partially by producing the decreases in the mRNA and protein levels of Nampt, since the Nampt inhibitor or the Nampt activator significantly exacerbated or attenuated the H2O2-induced cell death, respectively. Collectively, our study has indicated that oxidative stress can decrease both the mRNA and protein levels of Nampt, which has indicated a novel mechanism underlying the NAD+ deficiency in aging and under multiple pathological conditions. Our study has also indicated that the decreased Nampt levels contribute to the H2O2-induced cell death, suggesting a new mechanism underlying oxidative cell death.

scholarly journals RIP1/RIP3/MLKL Mediates Myocardial Function Through Necroptosis in Experimental Autoimmune Myocarditis

2021 ◽  
Vol 8 ◽  
Author(s):  
Yujing Wu ◽  
Zhenzhong Zheng ◽  
Xiantong Cao ◽  
Qing Yang ◽  
Vikram Norton ◽  
...  
Keyword(s):  
Cell Death ◽  
Myocardial Function ◽  
Viral Myocarditis ◽  
Cardiac Myosin ◽  
Autoimmune Myocarditis ◽  
Potential Therapeutic Target ◽  
Inflammatory Infiltration ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune

Cardiomyopathy often leads to dilated cardiomyopathy (DCM) when caused by viral myocarditis. Apoptosis is long considered as the principal process of cell death in cardiomyocytes, but programmed necrosis or necroptosis is recently believed to play an important role in cardiomyocyte cell death. We investigated the role of necroptosis and its interdependency with other processes of cell death, autophagy, and apoptosis in a rat system of experimental autoimmune myocarditis (EAM). We successfully created a rat model system of EAM by injecting porcine cardiac myosin (PCM) and showed that in EAM, all three forms of cell death increase considerably, resulting in the deterioration of cardiac conditions with an increase in inflammatory infiltration in cardiomyocytes. To explore whether necroptosis occurs in EAM rats independent of autophagy, we treated EAM rats with a RIP1/RIP3/MLKL kinase-mediated necroptosis inhibitor, Necrostatin-1 (Nec-1). In Nec-1 treated rats, cell death proceeds through apoptosis but has no significant effect on autophagy. In contrast, autophagy inhibitor 3-Methyl Adenine (3-MA) increases necroptosis, implying that blockage of autophagy must be compensated through necroptosis. Caspase 8 inhibitor zVAD-fmk blocks apoptosis but increases both necroptosis and autophagy. However, all necroptosis, apoptosis, and autophagy inhibitors independently reduce inflammatory infiltration in cardiomyocytes and improve cardiac conditions. Since apoptosis or autophagy is involved in many important cellular aspects, instead of suppressing these two major cell death processes, Nec1 can be developed as a potential therapeutic target for inflammatory myocarditis.

scholarly journals Hydrogen Peroxide Causes Cell Death via Increased Transcription of HOXB13 in Human Lung Epithelial A549 Cells

Toxics ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 78
Author(s):  
Naoki Endo ◽  
Takashi Toyama ◽  
Akira Naganuma ◽  
Yoshiro Saito ◽  
Gi-Wook Hwang
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Cell Death ◽  
Human Lung ◽  
A549 Cells ◽  
Protein Levels ◽  
Intracellular Ros ◽  
Lung Epithelial ◽  
Homeobox Protein

Although homeobox protein B13 (HOXB13) is an oncogenic transcription factor, its role in stress response has rarely been examined. We previously reported that knockdown of HOXB13 reduces the cytotoxicity caused by various oxidative stress inducers. Here, we studied the role of HOXB13 in cytotoxicity caused by hydrogen peroxide in human lung epithelial A549 cells. The knockdown of HOXB13 reduced hydrogen peroxide-induced cytotoxicity; however, this phenomenon was largely absent in the presence of antioxidants (Trolox or N-acetyl cysteine (NAC)). This suggests that HOXB13 may be involved in the cytotoxicity caused by hydrogen peroxide via the production of reactive oxygen species (ROS). Hydrogen peroxide also increased both the mRNA and protein levels of HOXB13. However, these increases were rarely observed in the presence of a transcriptional inhibitor, which suggests that hydrogen peroxide increases protein levels via increased transcription of HOXB13. Furthermore, cell death occurred in A549 cells that highly expressed HOXB13. However, this cell death was mostly inhibited by treatment with antioxidants. Taken together, our findings indicate that HOXB13 may be a novel factor involved in the induction of oxidative stress, which causes cell death via intracellular ROS production.

Sign in / Sign up

Export Citation Format

Share Document