Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells

Gulappa, Thippeswamy; Reddy, Ramadevi Subramani; Suman, Suman; Nyakeriga, Alice M.; Damodaran, Chendil

doi:10.1016/j.canlet.2013.05.014

Cited by 39 publications

(29 citation statements)

References 46 publications

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“…Our observation that D-gal-induced S phase arrest in cell cycle and p21 up-regulation (Fig.1 D-F) was in agreement with the previous reports that the cancer cells were treated with the chemicals [14]. p21 is an inhibitor of CDKs and its up-expression usually induces cell cycle arrest at the G1 phase by inhibiting CDKs activity [15], however it also directly inhibit DNA synthesis by binding to proliferating cell nuclear antigen (PCNA) [16], which induce S phage arrest. Additionally, it was proved that the expression of p21 can be induced by DNA-damaging agents via the ATM-chk2-p21 pathway [17].…”

Section: Discussionsupporting

confidence: 92%

Mitochondrial Impairment Mechanism in D-galactose-induced Senescence in Experimental Fibroblast Cell Model

Ye¹,

Cao²,

Tang³

et al. 2016

Proceedings of the 2016 International Conference on Biological Sciences and Technology

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Abstract.To establish an effective model for cellular senescence, human embryo lung fibroblast cells (MRC-5) were cultured in D-galactose (D-Gal) medium respectively, as control, same concentration of D-glucose (D-Glu) was used. Decrease in cell proliferation, increase in senescence associated β-galactosidase activity, up-expression of p21 protein, and cell cycle arrest at S-phage were observed in D-Gal-treated cells. Meanwhile, D-Gal-treated cells showed the significant increased ROS and MDA level and decreased SOD activity. Furthermore, mitochondrial impairment and decrease in efficiency of oxidative phosphorylation (OXPHOS) was induced by D-Gal as evidenced by the decreased transmembrane potential, reduction of ATP production and changes of respiration function. Additionally, the significant decrease of mitochondrial quantity, mitochondrial DNA (mtDNA) copy number and increased mtDNA damage were detected in D-Gal-treated cells. Our data demonstrate that D-Gal induces mitochondrial oxidative impairment associated with increased generation of ROS, ultimately inhibiting the ATP synthesis which contributes to premature cellular senescence.

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Section: Discussionsupporting

confidence: 92%

Mitochondrial Impairment Mechanism in D-galactose-induced Senescence in Experimental Fibroblast Cell Model

Ye¹,

Cao²,

Tang³

et al. 2016

Proceedings of the 2016 International Conference on Biological Sciences and Technology

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“…Thus, we here continued to focus on the molecular mechanism of cell cycle arrest in PCa cells induced by formononetin. The four phases (G1, S, G2, and M phases) of the cell cycle are sequentially transitioned in response to growth factor or oncogenic stimulation, including cyclins, the regulatory units, and cyclin-dependent kinases (CDKs), the catalytic units [24,][25]. Among them, cyclin D and E, together with CDK2, CDK4, or CDK6, play major parts in the replication of DNA and mitosis via the regulation of G0/G1 phase of the cell cycle [26].…”

Section: Discussionmentioning

confidence: 99%

Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells

Zhao

et al. 2014

Cell Physiol Biochem

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Background: Formononetin is an O-methylated isoflavone isolated from the root of Astragalus membranaceus. It has already been reported that formononetin could inhibit cell proliferation and induce cell apoptosis in several cancers, including prostate cancer. This study aimed to further investigate whether cell cycle arrest is involved in formononetin-mediated antitumor effect in human prostate cancer cells, along with the underlying molecular mechanism. Methods: Human prostate cancer cells PC-3 and DU145 were respectively treated with various concentrations of formononetin. The inhibitory effect of formononetin on proliferation of prostate cancer cells was determined using MTT assays and flow cytometry. Next, formononetin-induced alterations in cyclin D1, CDK4 and Akt expression in PC-3 cells were detected by real-time PCR and western blot. Results: Formononetin dose-dependently inhibited prostate cancer cell proliferation via the induction of cell cycle arrest at G0/G1 phase in vitro, which was more evident in PC-3 cells. Meanwhile, concomitant with reduced phosphorylation of Akt in PC-3 cells, formononetin remarkably downregulated expression levels of cyclin D1 and CDK4 in a dose-dependent manner. More interestingly, in the in vivo studies, formononetin showed a noticeable inhibition of tumor growth in recipient mice. Conclusion: Formononetin could exhibit inhibitory activity against human prostate cancer cells in vivo and in vitro, which is associated with G1 cell cycle arrest by inactivation of Akt/cyclin D1/CDK4. Therefore, formononetin may be used as a candidate agent for clinical treatment of prostate cancer in the future.

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“…We hypothesized that NCI-H460 exposure to toxic (80 nM), therapeutic (40 nM) and sub-therapeutic (25 and 10 nM) concentrations of digitoxin is associated with changes in the cellular viability that can be monitored using an individual cell as a primary transducer and recording its real-time alterations in morphology and adhesion profile. Further, based on the key role of the cyclin-dependent kinase-4 (CDK4) in regulation of cell proliferation and cell cycle (Gulappa et al, 2013; Si and Liu, 2001), we hypothesized that exposure to digitoxin targets cellular adhesion pathways in a dose and time-dependent manner by sequestering CDK4 in the cytoplasm and thus reducing its nuclear levels. Further, CDK4 association with viable candidates responsible for cellular junctions formation can be monitored in real-time as a change in the cellular attachment profile.…”

Section: Introductionmentioning

confidence: 99%

Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells

Eldawud

Stueckle

Manivannan

et al. 2014

Biosensors and Bioelectronics

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Digitoxin belongs to a naturally occurring class of cardiac glycosides (CG); digitoxin is clinically approved for heart failure and known for its anti-cancer effects against non-small lung cancer cells (NSCLC). However, concerns associated with its narrow therapeutic index and its concentration-dependent mechanism of action are rising. Thus, before digitoxin implementation in designing and developing safer and more effective CG-based anti-cancer therapies, its pharmacological and safety profiles need to be fully elucidated. In this research we used a combinatorial approach to evaluate the anti-cancer mechanisms of digitoxin in real-time. Our approach employed a non-invasive electric cell impedance sensing technique as a proxy to monitor NSCLC behavior post-exposure to toxic, therapeutic and sub-therapeutic concentrations of the drug. By developing structure–function combinatorial relations we showed that digitoxin targets cancer cells in a time and dose-dependant manner by activating pro-apoptotic and anti-proliferative signaling cascades that results in strengthening cellular adhesion and sequestration of key regulatory proliferation protein from the nucleus.

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Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells

Cited by 39 publications

References 46 publications

Mitochondrial Impairment Mechanism in D-galactose-induced Senescence in Experimental Fibroblast Cell Model

Mitochondrial Impairment Mechanism in D-galactose-induced Senescence in Experimental Fibroblast Cell Model

Formononetin Promotes Cell Cycle Arrest via Downregulation of Akt/Cyclin D1/CDK4 in Human Prostate Cancer Cells

Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells

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