Fueling the Cycle: CDKs in Carbon and Energy Metabolism

Solaki, Maria; Ewald, Jennifer C.

doi:10.3389/fcell.2018.00093

Cited by 43 publications

(30 citation statements)

References 55 publications

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“…Along this pathway, the effector E2F contributes to the switch from oxidative to glycolytic metabolism, by inducing the expression of glycolytic enzymes, such as phosphofructokinase, while down-regulating the expression of oxidative genes [9]. In addition, CDK4 and 6 as well as Cyclin D have been demonstrated to control energy metabolism, directly phosphorylating some metabolic enzymes or modulating the activity of metabolic regulators such as AMP-activated protein kinase (AMPK) [10]. Therefore, it is not surprising that the inhibition of the CDK4/6-Cyclin D/Rb/E2F pathway may exert multiple effects on cell energy metabolism [8].…”

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Bonelli

Terenziani

Zoppi

et al. 2020

IJMS

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Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

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Section: Introductionmentioning

confidence: 99%

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Bonelli

Terenziani

Zoppi

et al. 2020

IJMS

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“…Hanahan and Weinberg stated eight features of cancers known as the hallmarks of cancer . Current knowledge strongly supports that CDK dysregulation is implicated in several hallmarks of cancer such as sustaining proliferative signalling, resisting cell death, inducing angiogenesis, activating invasion and metastasis, and energy metabolism …”

Section: Cdks and Oral Carcinogenesismentioning

confidence: 99%

“…17 Current knowledge strongly supports that CDK dysregulation is implicated in several hallmarks of cancer such as sustaining proliferative signalling, 18 resisting cell death, 16 inducing angiogenesis, 19 activating invasion and metastasis, 20 and energy metabolism. 21 CDKs are a family of protein kinases with multiple functions, one of which is to regulate the cell cycle ( Figure 1). 22 Specifically, they act as checkpoints and drivers for the smooth transition from one phase to the next.…”

Section: Cdk S and Or Al C Arcinog Ene S Ismentioning

confidence: 99%

The role of cyclin‐dependent kinases in oral potentially malignant disorders and oral squamous cell carcinoma

Kujan

Huang

Ravindran

et al. 2019

J Oral Pathology Medicine

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Oral squamous cell carcinoma (OSCC) is a major global health problem with a relatively low‐moderate 5‐year survival rate. OSCC is often preceded by lesions and conditions known as oral potentially malignant disorders (OPMDs) that have an increased risk of malignant transformation. Despite advances in diagnostic technology and cancer research, the prognosis of OSCC remains poor as it is frequently detected a late stage. Understanding the molecular pathways involved in oral carcinogenesis provides a platform to identify biomarkers that may allow the early detection of OSCC and accurate prediction of the malignant potential of OPMDs. In addition, specific molecular inhibitors can be developed to target these important pathways and allow advanced therapeutic management to improve the prognosis of this malignancy. A common feature across a number of different cancers is the dysfunction of cell cycle moderator proteins known as cyclin‐dependent kinases. This review summarises the current literature regarding the role of cyclin‐dependent kinases in oral carcinogenesis with a particular focus on cyclin‐dependent kinases 4 (CDK4) and 6 (CDK6). This is of particular relevance as CDK4 and CDK6 inhibitors have shown some promising results in other cancer types and are interesting potential treatments for OSCC.

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“…G1/S-specific cyclin-E1 (CCNE) is a member of cyclin family, which cooperate with CDK2 to regulate the eukaryotic cell cycle (45). The role of CDKs in regulating energy metabolism especially glycolysis is noticed.…”

Section: Introductionmentioning

confidence: 99%

LncRNA-BLACAT1 Facilitates Proliferation, Migration and Aerobic Glycolysis of Pancreatic Cancer Cells by Repressing CDKN1C via EZH2-Induced H3K27me3

et al. 2020

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Objective: To investigate the role of lncRNA-BLACAT1 in promoting H3K27 trimethylation of CDKN1C gene by recruiting EZH2 to regulate CCNE on glycolysis and mitochondrial oxidative phosphorylation of pancreatic cancer (PC) cells. Methods: Following bioinformatic prediction, EZH2 and BLACAT1 in PC cells were interfered, and cells proliferation, migration and invasion in each group were detected. Western blotting detected the expression of key proteins of mitochondrial complex. The sub-cellular localization of BLACAT1 was tested, followed by testing the binding of CDKN1C and BLACAT1 with EZH2, followed by in vivo verification. Results: Based on bioinformatic prediction, EZH2 and BLACAT1 were highly expressed in PC, while CDKN1C was lowly expressed (all P < 0.05). Interference with EZH2 and BLACAT1 inhibited cell proliferation, migration and aerobic glycolysis, and promoted mitochondrial oxidative phosphorylation (all P < 0.05). BLACAT1 promoted H3K27 trimethylation of CDKN1C through recruiting EZH2 (all P < 0.05). In vivo results showed that BLACAT1 interference inhibited tumor formation (all P < 0.05). Conclusion: Interference with BLACAT1 inhibits H3K27 trimethylation of CDKN1C gene by blocking EZH2 recruitment to promote CDKN1C expression and inhibit CCNE expression, thus suppressing PC cell proliferation, migration and aerobic glycolysis, and promoting mitochondrial oxidative phosphorylation.

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Fueling the Cycle: CDKs in Carbon and Energy Metabolism

Cited by 43 publications

References 55 publications

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

The role of cyclin‐dependent kinases in oral potentially malignant disorders and oral squamous cell carcinoma

LncRNA-BLACAT1 Facilitates Proliferation, Migration and Aerobic Glycolysis of Pancreatic Cancer Cells by Repressing CDKN1C via EZH2-Induced H3K27me3

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