sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1α signaling pathways

Kim, Boh Ram; Seo, Seung Hee; Park, Mi Sun; Lee, Jun Young; Kwon, Young Joo; Rho, Seung Bae

doi:10.18632/oncotarget.5570

Cited by 30 publications

(33 citation statements)

References 65 publications

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“…Furthermore, there are many newly reported researches emphasize on the crucial role of the target protein VEGFR2 in the VEGF/VEGFR2 mediated PI3K/Akt signal pathway verified by the VEGFR2, PI3K and Akt inhibitors [28–31]. However, some scientists thought PI3K may also play an important role in some occasions [59–63].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The co-immunoprecipitation was performed as reported previously [ 81 ]. Briefly, the total cell extracts were incubated with anti-Flag antibody and then precipitated with protein A-agarose [ 80 ].…”

Section: Methodsmentioning

confidence: 99%

IRF-1 Inhibits Angiogenic Activity of HPV16 E6 Oncoprotein in Cervical Cancer

Rho

Lee

Byun

et al. 2020

IJMS

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HPV16 E6 oncoprotein is a member of the human papillomavirus (HPV) family that contributes to enhanced cellular proliferation and risk of cervical cancer progression via viral infection. In this study, interferon regulatory factor-1 (IRF-1) regulates cell growth inhibition and transcription factors in immune response, and acts as an HPV16 E6-binding cellular molecule. Over-expression of HPV16 E6 elevated cell growth by attenuating IRF-1-induced apoptosis and repressing p21 and p53 expression, but activating cyclin D1 and nuclear factor kappa B (NF-κB) expression. The promoter activities of p21 and p53 were suppressed, whereas NF-κB activities were increased by HPV16 E6. Additionally, the cell viability of HPV16 E6 was diminished by IRF-1 in a dose-dependent manner. We found that HPV16 E6 activated vascular endothelial growth factor (VEGF)-induced endothelial cell migration and proliferation as well as phosphorylation of VEGFR-2 via direct interaction in vitro. HPV16 E6 exhibited potent pro-angiogenic activity and clearly enhanced the levels of hypoxia-inducible factor-1α (HIF-1α). By contrast, the loss of function of HPV16 E6 by siRNA-mediated knockdown inhibited the cellular events. These data provide direct evidence that HPV16 E6 facilitates tumour growth and angiogenesis. HPV16 E6 also activates the PI3K/mTOR signalling cascades, and IRF-1 suppresses HPV16 E6-induced tumourigenesis and angiogenesis. Collectively, these findings suggest a biological mechanism underlying the HPV16 E6-related activity in cervical tumourigenesis.

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“…In addition, the expression of sMEK1 is remarkably decreased in ovarian and cervical cancer patient tissues, as well as in cancer cell lines, and is hypermethylated (36). Recently, we reported that sMEK1 inhibits endothelial cell proliferation and angiogenesis by suppressing VEGFR-2-mediated PI3K/Akt/eNOS signaling pathway in ovarian tumors (37). More specifically, protein phosphorylation/dephosphorylation plays an important role in various cellular conditions involved in the molecular basis for diseases such as diabetes, stroke, hypertension, and unusual movements within the cardiovascular system.…”

Section: Bmi-1 Interacts With Smek1 and Inactivates Smek1-induced Apomentioning

confidence: 99%

BMI-1 interacts with sMEK1 and inactivates sMEK1-induced apoptotic cell death

2016

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The B lymphoma Mo-MLV insertion region 1 homolog (BMI-1) protein is activated in various types of tumors and associated with cancer development and tumor progression. However, the working role of BMI-1 in cellular signaling is not understood completely. In this study, we revealed one possible biologic mechanism of BMI-1 in cancer progression in vitro using a human ovarian tumor cell system. Suppressor of MEK1 (sMEK1), a pivotal regulator involved in the cellular biological response mechanism, was identified as a BMI-1-binding protein. Ectopic expression of BMI-1 activated cell growth by reducing sMEK1-stimulated apoptotic cell death and suppressing p21, p27 and p53 expression, while enhancing cyclin D1, CDK4 and Bcl-2 expression. The effect of BMI-1 on cell cycle and apoptotic regulatory proteins was also confirmed via silencing of BMI-1 expression. Subsequently, the promoter activities of p21 and p53 were inactivated significantly. However, BMI-1 overexpression noticeably increased Bcl-2 and NF-κB activities. In addition, BMI-1 activated the PI3K/mTOR/4E-BP1 signaling pathways, and sMEK1 significantly inhibited BMI-1-stimulated oncogenesis. These insights provide evidence that BMI-1 activates cell growth and suppresses apoptosis. Collectively, our data indicate that BMI-1 plays a pivotal role in the progression of ovarian cancer, thus representing a novel target for antitumor therapy of ovarian cancer.

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sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1α signaling pathways

Cited by 30 publications

References 65 publications

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

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

IRF-1 Inhibits Angiogenic Activity of HPV16 E6 Oncoprotein in Cervical Cancer

BMI-1 interacts with sMEK1 and inactivates sMEK1-induced apoptotic cell death

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