scholarly journals p21cip1/waf1 Coordinates Autophagy, Proliferation and Apoptosis in Response to Metabolic Stress

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1112 ◽  
Author(s):  
Kanjoormana Manu ◽  
Pham Cao ◽  
Tin Chai ◽  
Patrick Casey ◽  
Mei Wang
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Biological Significance ◽  
Metabolic Stress ◽  
Exciting Field ◽  
Cell Functions ◽  
Metabolic Properties ◽  
Chemotherapeutic Treatment

Cancer cells possess metabolic properties that are different from benign cells. These unique characteristics have become attractive targets that are being actively investigated for cancer therapy. p21cip1/waf1, also known as Cyclin-Dependent Kinase inhibitor 1A, is encoded by the CDKN1A gene. It is a major p53 target gene involved in cell cycle progression that has been extensively evaluated. To date, p21 has been reported to regulate various cell functions, both dependent and independent of p53. Besides regulating the cell cycle, p21 also modulates apoptosis, induces senescence, and maintains cellular quiescence in response to various stimuli. p21 transcription is induced in response to stresses, including those from oxidative and chemotherapeutic treatment. A recent study has shown that in response to metabolic stresses such as nutrient and energy depletion, p21 expression is induced to regulate various cell functions. Despite the biological significance, the mechanism of p21 regulation in cancer adaptation to metabolic stress is underexplored and thus represents an exciting field. This review focuses on the recent development of p21 regulation in response to metabolic stress and its impact in inducing cell cycle arrest and death in cancer cells.

scholarly journals Advantages of Tyrosine Kinase Anti-Angiogenic Cediranib over Bevacizumab: Cell Cycle Abrogation and Synergy with Chemotherapy

2021 ◽  
Vol 14 (7) ◽  
pp. 682
Author(s):  
Jianling Bi ◽  
Garima Dixit ◽  
Yuping Zhang ◽  
Eric J. Devor ◽  
Haley A. Losh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Endometrial Cancer ◽  
Tyrosine Kinase ◽  
Cell Viability ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
M Cell

Angiogenesis plays a crucial role in tumor development and metastasis. Both bevacizumab and cediranib have demonstrated activity as single anti-angiogenic agents in endometrial cancer, though subsequent studies of bevacizumab combined with chemotherapy failed to improve outcomes compared to chemotherapy alone. Our objective was to compare the efficacy of cediranib and bevacizumab in endometrial cancer models. The cellular effects of bevacizumab and cediranib were examined in endometrial cancer cell lines using extracellular signal-related kinase (ERK) phosphorylation, ligand shedding, cell viability, and cell cycle progression as readouts. Cellular viability was also tested in eight patient-derived organoid models of endometrial cancer. Finally, we performed a phosphoproteomic array of 875 phosphoproteins to define the signaling changes related to bevacizumab versus cediranib. Cediranib but not bevacizumab blocked ligand-mediated ERK activation in endometrial cancer cells. In both cell lines and patient-derived organoids, neither bevacizumab nor cediranib alone had a notable effect on cell viability. Cediranib but not bevacizumab promoted marked cell death when combined with chemotherapy. Cell cycle analysis demonstrated an accumulation in mitosis after treatment with cediranib + chemotherapy, consistent with the abrogation of the G2/M checkpoint and subsequent mitotic catastrophe. Molecular analysis of key controllers of the G2/M cell cycle checkpoint confirmed its abrogation. Phosphoproteomic analysis revealed that bevacizumab and cediranib had both similar and unique effects on cell signaling that underlie their shared versus individual actions as anti-angiogenic agents. An anti-angiogenic tyrosine kinase inhibitor such as cediranib has the potential to be superior to bevacizumab in combination with chemotherapy.

scholarly journals Oncogenic role of ALX3 in cervical cancer cells through KDM2B-mediated histone demethylation of CDC25A

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jinhong Qi ◽  
Li Zhou ◽  
Dongqing Li ◽  
Jingyuan Yang ◽  
He Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Cervical Squamous Cell Carcinoma ◽  
Cycle Progression ◽  
Normal Tissues ◽  
Positive Regulator ◽  
Cervical Cancer Cells

Abstract Background Cell division cycle 25A (CDC25A) is a well-recognized regulator of cell cycle progression and is involved in cancer development. This work focused on the function of CDC25A in cervical cancer cell growth and the molecules involved. Methods A GEO dataset GSE63514 comprising data of cervical squamous cell carcinoma (CSCC) tissues was used to screen the aberrantly expressed genes in cervical cancer. The CDC25A expression in cancer and normal tissues was predicted in the GEPIA database and that in CSCC and normal cells was determined by RT-qPCR and western blot assays. Downregulation of CDC25A was introduced in CSCC cells to explore its function in cell growth and the cell cycle progression. The potential regulators of CDC25A activity and the possible involved signaling were explored. Results CDC25A was predicted to be overexpressed in CSCC, and high expression of CDC25A was observed in CSCC cells. Downregulation of CDC25A in ME180 and C33A cells reduced cell proliferation and blocked cell cycle progression, and it increased cell apoptosis. ALX3 was a positive regulator of CDC25A through transcription promotion. It recruited a histone demethylase, lysine demethylase 2B (KDM2B), to the CDC25A promoter, which enhanced CDC25A expression through demethylation of H3k4me3. Overexpression of ALX3 in cells blocked the inhibitory effects of CDC25A silencing. CDC25A was found as a positive regulator of the PI3K/Akt signaling pathway. Conclusion This study suggested that the ALX3 increased CDC25A expression through KDM2B-mediated demethylation of H3K4me3, which induced proliferation and cell cycle progression of cervical cancer cells.

scholarly journals Disruption of SHH signaling cascade by SBE attenuates lung cancer progression and sensitizes DDP treatment

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Jing Du ◽  
Weiwei Chen ◽  
Lijuan Yang ◽  
Juanjuan Dai ◽  
Jiwei Guo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cell Cycle Progression ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Cycle Progression ◽  
Shh Signaling ◽  
Shh Pathway

Abstract Deregulated Sonic Hedgehog (SHH) pathway facilitates the initiation, progression, and metastasis of Non-small cell lung cancer (NSCLC), confers drug resistance and renders a therapeutic interference option to lung cancer patients with poor prognosis. In this study, we screened and evaluated the specificity of a Chinese herb Scutellariabarbata D. Don extraction (SBE) in repressing SHH signaling pathway to block NSCLC progression. Our study confirmed that aberrant activation of the SHH signal pathway conferred more proliferative and invasive phenotypes to human lung cancer cells. This study revealed that SBE specifically repressed SHH signaling pathway to interfere the SHH-mediated NSCLC progression and metastasis via arresting cell cycle progression. We also found that SBE significantly sensitized lung cancer cells to chemotherapeutic agent DDP via repressing SHH components in vitro and in vivo. Mechanistic investigations indicated that SBE transcriptionally and specifically downregulated SMO and consequently attenuated the activities of GLI1 and its downstream targets in SHH signaling pathway, which interacted with cell cycle checkpoint enzymes to arrest cell cycle progression and lead to cellular growth inhibition and migration blockade. Collectively, our results suggest SBE as a novel drug candidate for NSCLC which specifically and sensitively targets SHH signaling pathway.

scholarly journals Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition

2005 ◽  
Vol 25 (13) ◽  
pp. 5725-5737 ◽  
Author(s):  
Kazuhiro Katayama ◽  
Naoya Fujita ◽  
Takashi Tsuruo
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Phosphorylation Site ◽  
Cytoplasmic Localization ◽  
M Cell ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
M Phase ◽  
Promote Cell Cycle Progression

ABSTRACT The serine/threonine kinase Akt is known to promote cell growth by regulating the cell cycle in G1 phase through activation of cyclin/Cdk kinases and inactivation of Cdk inhibitors. However, how the G2/M phase is regulated by Akt remains unclear. Here, we show that Akt counteracts the function of WEE1Hu. Inactivation of Akt by chemotherapeutic drugs or the phosphatidylinositide-3-OH kinase inhibitor LY294002 induced G2/M arrest together with the inhibitory phosphorylation of Cdc2. Because the increased Cdc2 phosphorylation was completely suppressed by wee1hu gene silencing, WEE1Hu was associated with G2/M arrest induced by Akt inactivation. Further analyses revealed that Akt directly bound to and phosphorylated WEE1Hu during the S to G2 phase. Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3θ but not 14-3-3β or -σ. These results indicate that Akt promotes G2/M cell cycle progression by inducing phosphorylation-dependent 14-3-3θ binding and cytoplasmic localization of WEE1Hu.

Paradoxical accumulation of the cyclin-dependent kinase inhibitor p27kip1 during the cAMP-dependent mitogenic stimulation of thyroid epithelial cells

1996 ◽  
Vol 109 (7) ◽  
pp. 1759-1764
Author(s):  
F. Depoortere ◽  
J.E. Dumont ◽  
P.P. Roger
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Concomitant Administration ◽  
Growth Stimulation ◽  
Positive Control ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Enhanced Expression

In different systems, cAMP either blocks or promotes cell cycle progression in mid to late G1 phase. Dog thyroid epithelial cells in primary culture constitute a model of positive control of DNA synthesis initiation and G0-S pre-replicative phase progression by cyclic AMP (cAMP) as a second messenger for thyrotropin (TSH). We report here that TSH markedly increases the expression of p27kip1, the inhibitor of the cell cycle and cyclin-dependent kinases. This effect was prevented by the concomitant administration of the cAMP-independent mitogens, epidermal growth factor (EGF)+serum. EGF+serum also slightly inhibited the weak basal accumulation of p27kip1. Nevertheless, in the case of stimulation by TSH alone, the cAMP-dependent cell cycle progression was fully compatible with the enhanced expression of p27kip1. This observation is paradoxical since a decrease of p27kip1 is generally associated with growth stimulation in other systems, and since a similar cAMP-dependent increase of p27kip1 in macrophages has been found responsible for mid-G1 cell cycle arrest. The opposite regulation of p27kip1 in response to TSH or EGF+serum in dog thyroid epithelial cells suggests a major difference at mid to late G1 stages between cAMP-dependent and cAMP-independent mitogenic pathways.

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