Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review)

Liu, Minghui; Liu, Hongyu; Chen, Jun

doi:10.3892/or.2018.6221

Cited by 63 publications

(56 citation statements)

References 76 publications

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“…Furthermore, a significant upregulation of ATG4A and ATG4D (proteins involved in autophagic cell death) was observed in the shFBXO2 group compared with the RL95-2-NC group ( Figure 7C ). We also found that inhibition of cyclin-dependent kinases by palbociclib (PD0332991, which specifically inhibits cyclin-dependent kinases 4 and 6 [CDK4/6]) ( Liu et al, 2018 ) reversed the effects of FBXO2 on proliferation of Ishikawa cells ( Figure 7D ). We also showed that the inhibition of 3-methyladenine (3-MA, an autophagy specific inhibitor) ( Luan et al, 2019 ) reversed the effects of FBXO2 on proliferation of RL95-2 cells ( Figure 7E ).…”

Section: Resultsmentioning

confidence: 78%

FBXO2 Promotes Proliferation of Endometrial Cancer by Ubiquitin-Mediated Degradation of FBN1 in the Regulation of the Cell Cycle and the Autophagy Pathway

Che

Jian

Wang

et al. 2020

Front. Cell Dev. Biol.

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F-box proteins, as substrates for S phase kinase-associated protein 1 (SKP1)-cullin 1 (CUL1)-F-box protein (SCF) ubiquitin ligase complexes, mediate the degradation of a large number of regulatory proteins involved in cancer processes. In this study, we found that F-box only protein 2 (FBXO2) was up-regulated in 21 endometrial carcinoma (EC) samples compared with five normal endometrium samples based on our Fudan cohort RNA-sequencing. The increased FBXO2 expression was associated with tumor stage, tumor grade, and histologic tumor type, and poor prognosis based on The Cancer Genome Atlas (TCGA) database. FBXO2 knockdown inhibited EC cell proliferation, and FBXO2 overexpression promoted the parental cell phenotype in vivo and in vitro . Fibrillin1 (FBN1) was also identified as a substrate for FBXO2 using a ubiquitination-proteome approach. In addition, promotion of EC proliferation by FBXO2 was regulated by specific proteins of the cell cycle (CDK4, CyclinD1, CyclinD2, and CyclinA1) and the autophagy signaling pathway (ATG4A and ATG4D) based on RNA sequencing (RNA-seq). We concluded that FBXO2 acts as an E3 ligase that targets FBN1 for ubiquitin-dependent degradation, so as to promote EC proliferation by regulating the cell cycle and the autophagy signaling pathway. Targeting FBXO2 may represent a potential therapeutic target for EC.

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Section: Resultsmentioning

confidence: 78%

FBXO2 Promotes Proliferation of Endometrial Cancer by Ubiquitin-Mediated Degradation of FBN1 in the Regulation of the Cell Cycle and the Autophagy Pathway

Che

Jian

Wang

et al. 2020

Front. Cell Dev. Biol.

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“…In tumor cells, an uncontrolled cell cycle is a significant indicator and the restriction function of the G1-S phase check point is reduced in cancer cells, which often leads to uncontrolled cell proliferation [ 24 ]. The data revealed that AsA decreased cyclin D, CDK4, p-RB and induced significant G0/G1-phase accumulation compared with the control in NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

A Marine Alkaloid, Ascomylactam A, Suppresses Lung Tumorigenesis via Inducing Cell Cycle G1/S Arrest through ROS/Akt/Rb Pathway

Wang

Huang

et al. 2020

Marine Drugs

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Ascomylactam A was reported for the first time as a new 13-membered-ring macrocyclic alkaloid in 2019 from the mangrove endophytic fungus Didymella sp. CYSK-4 from the South China Sea. The aim of our study was to delineate the effects of ascomylactam A (AsA) on lung cancer cells and explore the antitumor molecular mechanisms underlying of AsA. In vitro, AsA markedly inhibited the cell proliferation with half-maximal inhibitory concentration (IC50) values from 4 to 8 μM on six lung cancer cell lines, respectively. In vivo, AsA suppressed the tumor growth of A549, NCI-H460 and NCI-H1975 xenografts significantly in mice. Furthermore, by analyses of the soft agar colony formation, 5-ethynyl-20-deoxyuridine (EdU) assay, reactive oxygen species (ROS) imaging, flow cytometry and Western blotting, AsA demonstrated the ability to induce cell cycle arrest in G1 and G1/S phases by increasing ROS generation and decreasing of Akt activity. Conversely, ROS inhibitors and overexpression of Akt could decrease cell growth inhibition and cell cycle arrest induced by AsA. Therefore, we believe that AsA blocks the cell cycle via an ROS-dependent Akt/Cyclin D1/Rb signaling pathway, which consequently leads to the observed antitumor effect both in vitro and in vivo. Our results suggest a novel leading compound for antitumor drug development.

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“…The transition of G1 to S phase is a key step in the cell cycle process and plays an important role in developing most of the tumors. Suppressing G1/S transition may provide an attractive therapeutic target to stop cancer cells from proliferating [28]. Previously, a study reported that the down-regulation of cyclin H-CDK7 was implicated in the arrest of liver cancer cells in the G1 phase [29].…”

Section: Discussionmentioning

confidence: 99%

Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer

Chen

Yang

et al. 2020

Cancer Cell Int

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Background: Cell cycle dysregulation plays a key role in the pathogenesis of malignant tumors. As a part of the CDKactivating kinase (CAK) trimeric complex, cyclin H is necessary to regulate the cell cycle and proliferation. This investigation aims to characterize the clinical significance and the biological functions of cyclin H in ovarian cancer. Methods: Immunohistochemical staining was performed on 60 ovarian cancer cases, and a correlation between cyclin H expression and the clinical characteristics of ovarian cancer was analyzed. The function of cyclin H in ovarian cancer was further explored using HO8910 cells and a subcutaneous xenograft model of nude mice. Result: Cyclin H was slightly expressed in grade 1 ovarian cancer but highly expressed in grade 2 and grade 3 cancerous tissues. The Spearman's rank correlation analysis showed that the expression of cyclin H is positively correlated with the tumor grade, the FIGO stage, histological grade, and the peritoneal metastasis of ovarian cancer and is also positively correlated with the Ki67 and p-CDK2 in ovarian cancer. Additionally, we found that the five-year survival rate was higher in patients expressing low cyclin H than those expressing high cyclin H. Further, knockdown of cyclin H was achieved using an shRNA in HO8910 ovarian cancer cell line. Silencing cyclin H resulted in a G1/S cell cycle arrest in ovarian cancer cells suppressing its growth. The Ki67 expression was also decreased in cyclin H silenced ovarian cancer. Conclusion: These results suggest that high expression of cyclin H predicts the poor prognosis and promotes the growth of ovarian cancer by regulating the cell cycle.

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Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review)

Cited by 63 publications

References 76 publications

FBXO2 Promotes Proliferation of Endometrial Cancer by Ubiquitin-Mediated Degradation of FBN1 in the Regulation of the Cell Cycle and the Autophagy Pathway

FBXO2 Promotes Proliferation of Endometrial Cancer by Ubiquitin-Mediated Degradation of FBN1 in the Regulation of the Cell Cycle and the Autophagy Pathway

A Marine Alkaloid, Ascomylactam A, Suppresses Lung Tumorigenesis via Inducing Cell Cycle G1/S Arrest through ROS/Akt/Rb Pathway

Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer

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