Lapatinib induces p27<sup>Kip1</sup>-dependent G₁ arrest through both transcriptional and post-translational mechanisms

Tang, Lin; Wang, Yucai; Ström, Anders; Gustafsson, Jan Åke; Guan, Xiaoxiang

doi:10.4161/cc.25728

Cited by 35 publications

(36 citation statements)

References 55 publications

(57 reference statements)

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“…p27 Kip1 (p27) is a key cell-cycle regulator, which negatively regulates cell cycle progression via inhibiting the cyclinE/CDK2 complexes directly. 17,18 The activity of p27 is controlled by its concentration, distribution among different cellular complexes, and its cellular location. 19,20 The final step in glycolysis is catalyzed by Pyruvate kinase (PK) via transferring the phosphate from phosphoenolpyruvate (PEP) to ADP, thereby generating pyruvate and ATP.…”

Section: Introductionmentioning

confidence: 99%

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

et al. 2015

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Department of Stomatology; Affiliated Hospital of Nantong University, Nantong; Nantong University; 226001, Nantong, Jiangsu, PR China y These authors equally contributed to this work, and should be considered as joint first authors.Keywords: astrocyte proliferation, b-catenin, p27, PKM2, spinal cord injuryAbbreviations: CNS, Central nervous system; CDKs, cyclin-dependent kinases; CAK, CDK activating kinase; E2F, E2 promoter-binding protein dimerization partners; GFAP, Glial fibrillary acidic protein; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; NeuN, Neuronal nuclei; PCNA, Proliferating cell nuclear antigen; PEP, phosphoenolpyruvate; PK, Pyruvate kinase; PKM2, pyruvate kinase M2; pRb, protein retinoblastoma; SCI, Spinal cord injury; EGFR, Epidermal growth factor receptor.Aberrant functionality of the cell cycle has been implicated in the pathology of traumatic SCI. Although it has been reported that the expressions of various cell cycle related proteins were altered significantly following SCI, detailed information on the subject remains largely unclear. The embryonic pyruvate kinase M2 (PKM2) is an important metabolic kinase in aerobic glycolysis or the warburg effect, however, its functions in central nervous system (CNS) injury remains elusive. Here we demonstrate that PKM2 was not only significantly upregulated by western blot and immunohistochemistry but certain traumatic stimuli also induced translocation of PKM2 into the nucleus in astrocytes following spinal cord injury (SCI). Furthermore, the expression levels and localization of p-b-catenin, p27, cyclin D1 and PCNA were correlated with PKM2 after SCI. In vitro, we also found that PKM2 co-immunoprecipitation with p-b-catenin and p27 respectively. Knockdown of PKM2 apparently decreased the level of PCNA, cyclinD1, p27 in primary astrocyte cells. Taken together, our findings indicate that nuclear translocation of PKM2 promotes astrocytes proliferation after SCI through modulating cell cycle signaling. These discoveries firstly uncovered the role of PKM2 in spinal cord injury and provided a potential therapeutic target for CNS injury and repair.

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Section: Introductionmentioning

confidence: 99%

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

et al. 2015

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“…As a dual inhibitor of EGFR and Her‐2, lapatinib could block, Her‐2 corresponding downstream pathway, which was confirmed in our experiment. The down regulation of Her‐2 led to an induction of p27, and lapatinib induced p27 expression at both transcriptional and post‐translational level (Tang et al, ; Raina et al, ). Therefore, these suggested that lapatinib could affect Her‐2 corresponding downstream pathway to induce p27 expression.…”

Section: Resultsmentioning

confidence: 99%

miR-1470 mediates lapatinib induced p27 upregulation by targeting c-jun

et al. 2015

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Our previous study indicated that lapatinib induces p27-dependent G(1) arrest through both transcriptional and post-translational mechanisms. Using miRNA microarray technology and quantitative RT-PCR, we further investigated the potential miRNAs that involved in p27 upregulation and Her-2 signaling pathway alteration with lapatinib treatment. A subset of 7 miRNAs was significantly affected in both 0.5 µM and 2.0 µM and 24 h and 48 h lapatinib treatment. Among them, only miR-1470, miR-126, and miR-1208 were identified in the Her-2 pathway after KEGG pathway analysis. However, luciferase reporter assay confirmed that miR-1470 directly recognized the 3'-untranslated region of c-jun transcripts, which was consistent with TargetScan analysis. miR-1470 significantly decreased c-jun expression, thus miR-1470 may repressc-jun activation of cyclinD1 expression, and consequently promoted the upregulation of p27, a key molecule in the cell cycle arrest. Taken together, the present study provided the first evidences that miR-1470 mediated lapatinib induced p27 upregulation by targeting c-jun.

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“…Evidence demonstrated that various cyclin and CDK are involved in drug resistance of cancers. Recently, Lapatinib has been reported to induce p27 (Kip1)-dependent G1 arrest (Tang et al, 2013). Another study showed that Lapatinib treatment suppressed RTKmediated signaling by regulating p53, p27, and cyclin D1 and thus led to cell-cycle arrest in breast cancer cells (Li et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Identifying Differentially Expressed Genes and Screening Small Molecule Drugs for Lapatinib-resistance of Breast Cancer by a Bioinformatics Strategy

Wu¹,

Zhang²,

Xie³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Lapatinib, a dual tyrosine kinase inhibitor that interrupts the epidermal growth factor receptor (EGFR) and HER2/neu pathways, has been indicated to have significant efficacy in treating HER2-positive breast cancer. However, acquired drug resistance has become a very serious clinical problem that hampers the use of this agent. In this study, we aimed to screen small molecule drugs that might reverse lapatinib-resistance of breast cancer by exploring differentially expressed genes (DEGs) via a bioinformatics method. Materials and Methods: We downloaded the gene expression profile of BT474-J4 (acquired lapatinib-resistant) and BT474 (lapatinib-sensitive) cell lines from the Gene Expression Omnibus (GEO) database and selected differentially expressed genes (DEGs) using dChip software. Then, gene ontology and pathway enrichment analyses were performed with the DAVID database. Finally, a connectivity map was utilized for predicting potential chemicals that reverse lapatinib-resistance. Results: A total of 1, 657 DEGs were obtained. These DEGs were enriched in 10 pathways, including cell cycling, regulation of actin cytoskeleton and focal adhesion associate examples. In addition, several small molecules were screened as the potential therapeutic agents capable of overcoming lapatinib-resistance. Conclusions: The results of our analysis provided a novel strategy for investigating the mechanism of lapatinib-resistance and identifying potential small molecule drugs for breast cancer treatment.

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Lapatinib induces p27^Kip1-dependent G₁ arrest through both transcriptional and post-translational mechanisms

Cited by 35 publications

References 55 publications

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

miR-1470 mediates lapatinib induced p27 upregulation by targeting c-jun

Identifying Differentially Expressed Genes and Screening Small Molecule Drugs for Lapatinib-resistance of Breast Cancer by a Bioinformatics Strategy

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Lapatinib induces p27Kip1-dependent G₁ arrest through both transcriptional and post-translational mechanisms

Cited by 35 publications

References 55 publications

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

Nuclear translocation of PKM2 modulates astrocyte proliferation via p27 and β-catenin pathway after spinal cord injury

miR-1470 mediates lapatinib induced p27 upregulation by targeting c-jun

Identifying Differentially Expressed Genes and Screening Small Molecule Drugs for Lapatinib-resistance of Breast Cancer by a Bioinformatics Strategy

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Lapatinib induces p27^Kip1-dependent G₁ arrest through both transcriptional and post-translational mechanisms