Mirk/Dyrk1B mediates G0/G1 to S phase cell cycle progression and cell survival involving MAPK/ERK signaling in human cancer cells

Gao, Jingchun; Zhao, Yi; Lv, Yunyi; Chen, Yamin; Wei, Bing; Tian, Jiang; Yang, Zeran; Kong, Fandou; Pang, Junfeng; Liu, Jiwei; Hong, Seonki

doi:10.1186/1475-2867-13-2

Cited by 38 publications

(41 citation statements)

References 20 publications

(36 reference statements)

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“…Besides, the same with Gao et al's [34] and Ko et al's [35] study, cyclinD1 was downregulated at 6 and 24 h with U0126 in both cell lines. Withal, we observed RAD001+U0126 combination have inhibitory effects on cyclinD1 expression in A549 and Calu-1 cell lines.…”

Section: Discussionsupporting

confidence: 84%

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

2015

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KRAS mutations are found in 15-25 % of patients with lung adenocarcinoma, and they lead to constitutive activation of KRAS signaling pathway that results in sustained cell proliferation. Currently, there are no direct anti-KRAS therapies available. Therefore, it is rational to target the downstream molecules of KRAS signaling pathway, which are mitogen-activated protein kinase (MAPK) signaling pathway (RAF-MEK-ERK) and PI3K pathway (PI3K-AKT-mTOR). Here, we examined the inhibition of both these pathways alone and in combination and analyzed the anti-proliferative and apoptotic events in KRAS mutant NSCLC cell lines, A549 and Calu-1. Cytotoxicity was determined by MTT assay after the cells were treated with LY294002 (PI3K inhibitor), U0126 (MEK inhibitor), and RAD001 (mTOR inhibitor) for 24 and 48 h. The expression levels of p-ERK, ERK, AKT, p-AKT, p53, cyclinD1, c-myc, p27(kip1), BAX, BIM, and GAPDH were detected by western blot after 6 and 24 h treatment. Although PI3K/mTOR inhibition is more effective in cytotoxicity in A549 and Calu-1 cells, MEK/mTOR inhibition markedly decreases cell proliferation protein marker expressions. Our data show that combined targeting of MEK and PI3K-AKT with mTOR is a better option than single agents alone for KRAS mutant NSCLC, thus opening the possibility of a beneficial treatment strategy in the future.

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Section: Discussionsupporting

confidence: 84%

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

2015

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“…In particular, Erk1/2 inhibition caused a dose-dependent decrease in the absolute number of living cells along with downregulation of cyclin D1 levels in both OSCC cell lines tested. These findings corroborate previous studies that demonstrated negative regulation of cell growth and cyclin D1 levels following Erk1/2 inhibition by means of U0126 treatment (44,47,55,56).…”

Section: Discussionsupporting

confidence: 82%

“…Notably, the increase in absolute cell number is accompanied by a relative increase in cyclin D1. In agreement, Gao et al suggested that activation of the c-Raf-MEK-Erk1/2 pathway leads to subsequent increase in cell cycle proteins (cyclin D1, p27kip1), accompanied by an increased growth rate and transition of cells from G0/G1 into the S phase of the cell cycle in both ovarian and non-small cell lung cancer (47). Similarly, Wang et al indicated that overexpression of activated Erk1/2 and cyclin D1 proteins are involved in oral tongue carcinogenesis (51).…”

Section: Discussionsupporting

confidence: 48%

“…For example, knockdown of serine/threonine kinase Mirk/Dyrk1B by siRNA in either ovarian cancer or non-small cell lung cancer (NSCLC) cells led to upregulated activation of c-Raf-MEK-ERK, followed by increased growth rate (47). Induction of anti-apoptotic proteins, such as Bcl2, Bclxl and inhibition of pro-apoptotic factors, including Bad, has been correlated with the oncogenic potential of ERK activity (48).…”

Section: Discussionmentioning

confidence: 99%

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Erk1/2 activation and modulation of STAT3 signaling in oral cancer

et al. 2014

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Abstract. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway possesses confirmed oncogenic potential in oral squamous cell carcinoma (OSCC). Crosstalk with other molecular pathways contributes to STAT3 regulation in cancer. The effects of mitogen-activated protein kinases (MAPKs) and particularly extracellular signal-regulated kinase 1/2 (Erk1/2) on STAT3 signaling in OSCC have not been thoroughly investigated. The present study examined the effects of Erk1/2 modulation on STAT3 signaling and cell growth in OSCC cells. Constitutive expression levels of phosphorylated (tyrosine and serine) and total STAT3, Erk1/2 and cyclin D1 were assessed in OSCC cell lines. Erk1/2 modulation was achieved by pharmacological agents; siRNA silencing against Erk1/2 was also performed. Cell proliferation and viability were assessed. Erk1/2 inhibition with either U0126 treatment or specific siRNA silencing resulted in decreases in p-ser STAT3 and cyclin D1 levels and increases in p-tyr STAT3 in OSCC cells. Moreover, Erk1/2 inhibition resulted in a dose-dependent reduction in OSCC cell growth and viability. Erk1/2 induction had the opposite effects. Taken together, these results are supportive of an active crosstalk between the oncogenic Erk1/2 and STAT3 pathways in OSCC, the significance of which requires further investigation.

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“…As a confirmation of on-target effects, the siRNAs were shown actually to knock down their cognate targets. Among the final candidates, DYRK1B a developmentally important kinase (11), that has been implicated in cell cycle control (12, 13) and cancer (14-16), had the greatest effect on NKX3.1. DYRK1B interacted directly with the prostate suppressor protein and phosphorylated a key residue that signaled protein degradation.…”

Section: Introductionmentioning

confidence: 99%

The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase

Song

Silva²,

Koller

et al. 2015

Molecular Cancer Research

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NKX3.1 is a prostate specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Since NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high throughput screen was developed using a siRNA library for kinases that mediate NKX3.1 degradation. This approach identified several candidates of which DYRK1B, a kinase that is subject to gene amplification and overexpression in other cancers, had the greatest impact on NKX3.1 half-life. Mechanistically, NKX3.1 and DYRK1B were shown to interact via the DYRK1B kinase domain. In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine185, a residue critical for NKX3.1 steady state turnover. Lastly, small molecule inhibitors of DYRK1B prolonged NKX3.1 half-life. Thus, DYRK1B is a target for enzymatic inhibition in order to increase cellular NKX3.1. Implications DYRK1B is a promising and novel kinase target for prostate cancer treatment mediated by enhancing NKX3.1 levels.

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Mirk/Dyrk1B mediates G0/G1 to S phase cell cycle progression and cell survival involving MAPK/ERK signaling in human cancer cells

Cited by 38 publications

References 20 publications

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

Erk1/2 activation and modulation of STAT3 signaling in oral cancer

The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase

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