Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Nagel, Remco; Walsum, Marijke Stigter-van; Buijze, Marijke; Berg, Jaap van den; Meulen, Ida H. van der; Hodzic, Jasmina; Piersma, Sander R.; Pham, Thang V.; Jiménez, Connie R.; Beusechem, Victor W. van; Brakenhoff, Ruud H.

doi:10.1158/1535-7163.mct-14-0846

Cited by 33 publications

(28 citation statements)

References 36 publications

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“…Recent evidence from a variety of model systems has shown that, besides its primordial role in mitotic division, Gwl also contributes in a significant extent to tumorigenic processes (Alvarez-Fernandez et al, 2017;Uppada et al, 2018;Vera et al, 2015;Dahlhaus et al, 2016;Nagel et al, 2015). Upregulation of Gwl activity promotes cell transformation and increases cell proliferation in several immortalized cells lines and in primary human fibroblasts (Vera et al, 2015).…”

Section: Gwl and Cancermentioning

confidence: 99%

Greatwall kinase at a glance

Castro

Lorca

2018

Journal of Cell Science

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Mitosis is controlled by a subtle balance between kinase and phosphatase activities that involve the master mitotic kinase cyclin-B-Cdk1 and its antagonizing protein phosphatase 2A-B55 (PP2A-B55). Importantly, the Greatwall (Gwl; known as Mastl in mammals, Rim15 in budding yeast and Ppk18 in fission yeast) kinase pathway regulates PP2A-B55 activity by phosphorylating two proteins, cAMPregulated phosphoprotein 19 (Arpp19) and α-endosulfine (ENSA). This phosphorylation turns these proteins into potent inhibitors of PP2A-B55, thereby promoting a correct timing and progression of mitosis. In this Cell Science at a Glance article and the accompanying poster, we discuss how Gwl is regulated in space and time, and how the Gwl-Arpp19-ENSA-PP2A-B55 pathway plays an essential role in the control of M and S phases from yeast to human. We also summarize how Gwl modulates oncogenic properties of cells and how nutrient deprivation influences Gwl activity.

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Section: Gwl and Cancermentioning

confidence: 99%

Greatwall kinase at a glance

Castro

Lorca

2018

Journal of Cell Science

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“…In breast cancer, MASTL expression increases with advanced clinical stage and predicts poor survival (Álvarez-Fernández et al, 2018;Rogers et al, 2018;Wang et al, 2016;Yoon et al, 2018), with high MASTL levels positively correlating with increased tumor growth and metastasis in vivo (Álvarez-Fernández et al, 2018;Rogers et al, 2018;Vera et al, 2015). Moreover, knockdown of MASTL induces radiosensitivity (Nagel et al, 2015), which makes MASTL an appealing pharmacological target. However, the exact mechanism of how MASTL facilitates tumorigenicity remains unknown.…”

Section: Introductionmentioning

confidence: 99%

MASTL promotes cell contractility and motility through kinase-independent signaling

Taskinen

Närvä

Conway

et al. 2020

Journal of Cell Biology

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Microtubule-associated serine/threonine-protein kinase-like (MASTL) is a mitosis-accelerating kinase with emerging roles in cancer progression. However, possible cell cycle–independent mechanisms behind its oncogenicity remain ambiguous. Here, we identify MASTL as an activator of cell contractility and MRTF-A/SRF (myocardin-related transcription factor A/serum response factor) signaling. Depletion of MASTL increased cell spreading while reducing contractile actin stress fibers in normal and breast cancer cells and strongly impairing breast cancer cell motility and invasion. Transcriptome and proteome profiling revealed MASTL-regulated genes implicated in cell movement and actomyosin contraction, including Rho guanine nucleotide exchange factor 2 (GEF-H1, ARHGEF2) and MRTF-A target genes tropomyosin 4.2 (TPM4), vinculin (VCL), and nonmuscle myosin IIB (NM-2B, MYH10). Mechanistically, MASTL associated with MRTF-A and increased its nuclear retention and transcriptional activity. Importantly, MASTL kinase activity was not required for regulation of cell spreading or MRTF-A/SRF transcriptional activity. Taken together, we present a previously unknown kinase-independent role for MASTL as a regulator of cell adhesion, contractility, and MRTF-A/SRF activity.

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“…Lung cancer is a leading cause of cancer death worldwide, with a 5-year survival rate of 5–15% [1]. Non-small cell lung cancer (NSCLC), accounting for approximately 85% of all lung cancer cases, is the dominant type.…”

Section: Introductionmentioning

confidence: 99%

Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way

Xie

Liu

et al. 2016

BMC Cancer

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BackgroundThe study was designed to develop a platform to verify whether the extract of herbs combined with chemotherapy drugs play a synergistic role in anti-tumor effects, and to provide experimental evidence and theoretical reference for finding new effective sensitizers.MethodsInhibition of tanshinone IIA and adriamycin on the proliferation of A549, PC9 and HLF cells were assessed by CCK8 assays. The combination index (CI) was calculated with the Chou-Talalay method, based on the median-effect principle. Migration and invasion ability of A549 cells were determined by wound healing assay and transwell assay. Flow cytometry was used to detect the cell apoptosis and the distribution of cell cycles. TUNEL staining was used to detect the apoptotic cells. Immunofluorescence staining was used to detect the expression of Cleaved Caspase-3. Western blotting was used to detect the proteins expression of relative apoptotic signal pathways. CDOCKER module in DS 2.5 was used to detect the binding modes of the drugs and the proteins.ResultsBoth tanshinone IIA and adriamycin could inhibit the growth of A549, PC9, and HLF cells in a dose- and time-dependent manner, while the proliferative inhibition effect of tanshinone IIA on cells was much weaker than that of adriamycin. Different from the cancer cells, HLF cells displayed a stronger sensitivity to adriamycin, and a weaker sensitivity to tanshinone IIA. When tanshinone IIA combined with adriamycin at a ratio of 20:1, they exhibited a synergistic anti-proliferation effect on A549 and PC9 cells, but not in HLF cells. Tanshinone IIA combined with adriamycin could synergistically inhibit migration, induce apoptosis and arrest cell cycle at the S and G2 phases in A549 cells. Both groups of the single drug treatment and the drug combination up-regulated the expressions of Cleaved Caspase-3 and Bax, but down-regulated the expressions of VEGF, VEGFR2, p-PI3K, p-Akt, Bcl-2, and Caspase-3 protein. Compared with the single drug treatment groups, the drug combination groups were more statistically significant. The molecular docking algorithms indicated that tanshinone IIA could be docked into the active sites of all the tested proteins with H-bond and aromatic interactions, compared with that of adriamycin.ConclusionsTanshinone IIA can be developed as a novel agent in the postoperative adjuvant therapy combined with other anti-tumor agents, and improve the sensibility of chemotherapeutics for non-small cell lung cancer with fewer side effects. In addition, this experiment can not only provide a reference for the development of more effective anti-tumor medicine ingredients, but also build a platform for evaluating the anti-tumor effects of Chinese herbal medicines in combination with chemotherapy drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2921-x) contains supplementary material, which is available to authorized users.

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Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Cited by 33 publications

References 36 publications

Greatwall kinase at a glance

Greatwall kinase at a glance

MASTL promotes cell contractility and motility through kinase-independent signaling

Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way

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