Molecular Mechanisms of the Control of Cell Growth in Cancer

Cell Growth ◽  
1982 ◽  
pp. 673-714 ◽  
Author(s):  
Arthur B. Pardee
Keyword(s):  
Cell Growth ◽  
Molecular Mechanisms

Knockdown CYP2S1 inhibits lung cancer cells proliferation and migration

2021 ◽  
pp. 1-9
Author(s):  
Huan Guo ◽  
Baozhen Zeng ◽  
Liqiong Wang ◽  
Chunlei Ge ◽  
Xianglin Zuo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Lung Cancer Cells ◽  
Invasion And Migration ◽  
And Migration

BACKGROUND: The incidence of lung cancer in Yunnan area ranks firstly in the world and underlying molecular mechanisms of lung cancer in Yunnan region are still unclear. We screened a novel potential oncogene CYP2S1 used mRNA microassay and bioinformation database. The function of CYP2S1 in lung cancer has not been reported. OBJECTIVE: To investigate the functions of CYP2S1 in lung cancer. METHODS: Immunohistochemistry and Real-time PCR were used to verify the expression of CYP2S1. Colony formation and Transwell assays were used to determine cell proliferation, invasion and migration. Xenograft assays were used to detected cell growth in vivo. RESULTS: CYP2S1 is significantly up-regulated in lung cancer tissues and cells. Knockdown CYP2S1 in lung cancer cells resulted in decrease cell proliferation, invasion and migration in vitro. Animal experiments showed downregulation of CYP2S1 inhibited lung cancer cell growth in vivo. GSEA analysis suggested that CYP2S1 played functions by regulating E2F targets and G2M checkpoint pathway which involved in cell cycle. Kaplan-Meier analysis indicated that patients with high CYP2S1 had markedly shorter event overall survival (OS) time. CONCLUSIONS: Our data demonstrate that CYP2S1 exerts tumor suppressor function in lung cancer. The high expression of CYP2S1 is an unfavorable prognostic marker for patient survival.

scholarly journals Exploring the Intracrine Functions of VEGF-A

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Sophie Wiszniak ◽  
Quenten Schwarz
Keyword(s):  
Cell Growth ◽  
Molecular Mechanisms ◽  
Direct Action ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Vascular Endothelial ◽  
Signalling Molecule ◽  
Endothelial Growth Factor ◽  
Important Signalling Molecule ◽  
Vegf Signalling

Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed “intracrine”, and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics.

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
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.

scholarly journals MicroRNA-138 Inhibits Cell Growth, Invasion, and EMT of Non-Small Cell Lung Cancer via SOX4/p53 Feedback Loop

2018 ◽  
Vol 26 (3) ◽  
pp. 385-400 ◽  
Author(s):  
Dandan Li ◽  
Changjun He ◽  
Junfeng Wang ◽  
Yanbo Wang ◽  
Jianlong Bu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Small Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung

Many studies have shown that downregulation of miR-138 occurs in a variety of cancers including non-small cell lung cancer (NSCLC). However, the precise mechanisms of miR-138 in NSCLC have not been well clarified. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in NSCLC cell lines, discussing whether it could turn out to be a therapeutic biomarker of NSCLC in the future. In our study, we found that miR-138 is downregulated in NSCLC tissues and cell lines. Moreover, the low level of miR-138 was associated with increased expression of SOX4 in NSCLC tissues and cell lines. Upregulation of miR-138 significantly inhibited proliferation of NSCLC cells. In addition, invasion and EMT of NSCLC cells were suppressed by overexpression of miR-138. However, downregulation of miR-138 promoted cell growth and metastasis of NSCLC cells. Bioinformatics analysis predicted that SOX4 was a potential target gene of miR-138. Next, luciferase reporter assay confirmed that miR-138 could directly target SOX4. Consistent with the effect of miR-138, downregulation of SOX4 by siRNA inhibited proliferation, invasion, and EMT of NSCLC cells. Overexpression of SOX4 in NSCLC cells partially reversed the effect of miR-138 mimic. In addition, decreased SOX4 expression could increase the level of miR-138 via upregulation of p53. Introduction of miR-138 dramatically inhibited growth, invasion, and EMT of NSCLC cells through a SOX4/p53 feedback loop.

scholarly journals In Search of the Molecular Mechanisms Mediating the Inhibitory Effect of the GnRH Antagonist Degarelix on Human Prostate Cell Growth

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0120670 ◽  
Author(s):  
Monica Sakai ◽  
Daniel B. Martinez-Arguelles ◽  
Nathan H. Patterson ◽  
Pierre Chaurand ◽  
Vassilios Papadopoulos
Keyword(s):  
Cell Growth ◽  
Molecular Mechanisms ◽  
Gnrh Antagonist ◽  
Inhibitory Effect ◽  
Human Prostate ◽  
Prostate Cell

7-hydroxyfrullanolide, isolated from Sphaeranthus indicus, inhibits colorectal cancer cell growth by p53-dependent and -independent mechanism

2018 ◽  
Vol 40 (6) ◽  
pp. 791-804
Author(s):  
Praveen Pandey ◽  
Deepika Singh ◽  
Mohammad Hasanain ◽  
Raghib Ashraf ◽  
Mayank Maheshwari ◽  
...  
Keyword(s):  
Cell Growth ◽  
Anticancer Activity ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cancer Cell Growth ◽  
Apoptotic Pathway ◽  
Syngeneic Mouse Model ◽  
Sphaeranthus Indicus

Abstract Sphaeranthus indicus Linn. is commonly used in Indian traditional medicine for management of multiple pathological conditions. However, there are limited studies on anticancer activity of this plant and its underlying molecular mechanisms. Here, we isolated an active constituent, 7-hydroxyfrullanolide (7-HF), from the flowers of this plant, which showed promising chemotherapeutic potential. The compound was more effective in inhibiting in vitro proliferation of colon cancers cells through G2/M phase arrest than other cancer cell lines that were used in this study. Consistent with in vitro data, 7-HF caused substantial regression of tumour volume in a syngeneic mouse model of colon cancer. The molecule triggered extrinsic apoptotic pathway, which was evident as upregulation of DR4 and DR5 expression as well as induction of their downstream effector molecules (FADD, Caspase-8). Concurrent activation of intrinsic pathway was demonstrated with loss of ΔΨm to release pro-apoptotic cytochrome c from mitochondria and activation of downstream caspase cascades (Caspase -9, -3). Loss of p53 resulted in decreased sensitivity of cells towards pro-apoptotic effect of 7-HF with increased number of viable cells indicating p53-dependent arrest of cancer cell growth. This notion was further supported with 7-HF-mediated elevation of endogenous p53 level, decreased expression of MDM2 and transcriptional upregulation of p53 target genes in apoptotic pathway. However, 7-HF was equally effective in preventing progression of HCT116 p53+/+ and p53−/− cell derived xenografts in nude mice, which suggests that differences in p53 status may not influence its in vivo efficacy. Taken together, our results support 7-HF as a potential chemotherapeutic agent and provided a new mechanistic insight into its anticancer activity.

scholarly journals Signal transduction of vitamin K3 for pancreas cancer therapy

2011 ◽  
pp. 57-60
Author(s):  
Toshiyuki Tanahashi ◽  
Shinji Osada ◽  
Hisashi Imai ◽  
Yoshiyuki Sasaki ◽  
Takao Takahashi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Molecular Mechanisms ◽  
Pancreas Cancer ◽  
Advanced Pancreatic Cancer ◽  
Vitamin K3 ◽  
Inhibition Of Proliferation ◽  
Apoptosis Pathway ◽  
Erk Phosphorylation ◽  
Thiol Antioxidant

We characterized molecular mechanisms of vitamin K3 (VK3)-induced inhibition of proliferation to evaluate VK3 effectiveness in treating advanced pancreatic cancer. A novel endoscopic drug delivery system, ultrasound injection technique, was used to study local effects of VK3. VK3 inhibited pancreas cancer cell growth by rapid phosphorylation of growth factor receptor and cellular signal factors such as extracellular signal-regulated kinase. VK3 also activated apoptosis, and apoptosis inhibitor antagonized the apoptosis pathway without inhibiting cell growth. Thiol antioxidant treatment completely abrogated VK3-induced ERK but not JNK phosphorylation or inhibition of proliferation. Non-thiol antioxidant did not affect ERK phosphorylation or growth inhibitory actions. Arylation was considered the main mechanism of VK3-induced growth inhibition through ERK activation. VK3 may lead to favorable outcomes in the treatment of pancreatic tumors. Detection of ERK phosphorylation in tissue is important to predict VK3 effect. Endoscopic ultrasound-guided fine-needle injection may be beneficial for treating pancreatic cancer with VK3.

scholarly journals Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

2018 ◽  
Author(s):  
Evgeny Zatulovskiy ◽  
Daniel F. Berenson ◽  
Benjamin R. Topacio ◽  
Jan M. Skotheim
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Cell Size ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Inverse Correlation ◽  
Cell Types ◽  
Similar Amount ◽  
Cell Cycle Inhibitor

Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport1,2. Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division3–6. While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive7–12. Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. Rb is a stable protein that is synthesized during S and G2 phases in an amount that is independent of cell size. Equal partitioning to daughter cells of chromatin bound Rb then ensures that all cells at birth inherit a similar amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rb-dilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.

Abstract 263: Differential Effects of 17ß-Estradiol and 16a-Hydroxyestrone in Oxidative Stress and Proliferative Responses in Human Pulmonary Artery Smooth Muscle Cells - Implications in Pulmonary Arterial Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Katie Y Hood ◽  
Augusto C Montezano ◽  
Margaret R MacLean ◽  
Rhian M Touyz
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Arterial Hypertension ◽  
Cell Growth ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Antioxidant Systems ◽  
Ros Generation ◽  
Ros Production ◽  
Differential Effects ◽  
Pulmonary Arterial

Women develop pulmonary arterial hypertension (PAH) more frequently than men. This may relate, in part, to metabolism of 17β-estradiol (E2), leading to formation of the deleterious metabolite, 16α-hydroxyestrone (16α OHE1), which plays a role in the remodelling of pulmonary arteries. Molecular mechanisms whereby 16αOHE1 influences PASMC remodelling are unclear but ROS may be important, since oxidative stress has been implicated in the pathogenesis of PAH. We hypothesised that E2 and 16αOHE1 leads to Nox-induced ROS production, which promotes PASMC damage. Cultured PASMCs were stimulated with either E2 (1nM) or 16αOHE1 (1nM) in the presence/absence of EHT1864 (100μM, Rac1 inhibitor) or tempol (antioxidant; 10μM). ROS production was assessed by chemiluminescence (O2-) and Amplex Red (H2O2). Antioxidants (thioredoxin, peroxiredoxin 1 and NQ01), regulators of Nrf2 (BACH1, Nrf2) and, marker of cell growth (PCNA) were determined by immunoblotting. E2 increased O2- production at 4h (219 ± 30% vs vehicle; p<0.05), an effect blocked by EHT1864 and tempol. E2 also increased H2O2 generation (152 ± 4%; p<0.05). Thioredoxin, NQ01 and peroxiredoxin1 (71 ± 6%; 78 ± 9%; 69 ± 8%; p<0.05 respectively) levels were decreased by E2 as was PCNA expression (72 ± 2%; p<0.05). 16αOHE1 exhibited a rapid (5 min) and exaggerated increase in ROS production (355 ± 41%; p<0.05), blocked by tempol and EHT1864. This was associated with an increase in Nox4 expression (139 ± 11% vs vehicle, p<0.05). 16αOHE1 increased BACH1, (129 ± 3%; p<0.05), a competitor of Nrf2, which was decreased (92 ± 2%). In contrast, thioredoxin expression was increased by 16aOHE1 (154 ± 22%; p<0.05). PCNA (150 ± 5%) expression was also increased after exposure to 16αOHE1. In conclusion, E2 and 16αOHE1 have differential effects on redox processes associated with PASMC growth. Whereas E2 stimulates ROS production in a slow and sustained manner without effect on cell growth, 16αOHE1 upregulates Nox4 with associated rapid increase in ROS generation and downregulation of antioxidant systems, affecting proliferation. Our findings suggest that E2 -derived metabolites may promote a pro-proliferative PASMC phenotype through Nox4-derived ROS generation. These deleterious effects may impact on vascular remodeling in PAH.

YAP mediates the positive regulation of hnRNPK on the lung adenocarcinoma H1299 cell growth

2019 ◽  
Vol 51 (7) ◽  
pp. 677-687
Author(s):  
Lipei Xu ◽  
Tingting Zhang ◽  
Wensi Huang ◽  
Xiaohui Liu ◽  
Junlei Lu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Growth ◽  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Contact Inhibition ◽  
Negative Regulator ◽  
Cell Contact ◽  
Reporter System ◽  
H1299 Cell ◽  
Multifunctional Protein

AbstractLung cancer is the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) accounts for 80%–85% of diagnostic cases. The molecular mechanisms of NSCLC pathogenesis are not well understood. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a multifunctional protein that regulates gene expression and signal transduction and closely associated with tumorigenesis, but its mechanism of action in the pathogenesis of NSCLC is unclear. In this study, we observed that the expression pattern of hnRNPK in H1299 lung adenocarcinoma cells varied depending on the cell density in culture. Moreover, hnRNPK stimulated the ability of proliferation and colony formation of H1299 cells, which is important for the multilayered cell growth in culture. We further investigated whether there is an association between hnRNPK and the elements involved in the cell contact inhibition pathway. By using quantitative reverse transcriptase-polymerase chain reaction assay and a YAP activity reporter system, we found that hnRNPK upregulated the mRNA and protein levels and transcriptional activity of Yes-associated protein 1 (YAP), a master negative regulator of Hippo contact inhibition pathway. Furthermore, YAP knockdown with siRNA abolished the stimulatory effect of hnRNPK on H1299 cell proliferation. These results suggested that YAP could be one of the effectors of hnRNPK. Our data may provide new clues for further understanding the biological functions of hnRNPK, particularly in the context of lung adenocarcinoma oncogenesis.

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