The MAPK pathway as an apoptosis enhancer in melanoma

Haydn, Johannes M.; Hufnagel, Anita; Grimm, Johannes; Maurus, Katja; Schartl, Manfred; Meierjohann, Svenja

doi:10.18632/oncotarget.2079

Cited by 34 publications

(24 citation statements)

References 57 publications

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“…The combination treatment exhibited a stronger inhibitory effect on Ras/Raf/MEK/ERK1/2 pathway and PI3K level than TPT or DT-13 alone in BGC-823 (Figure 2B) and SGC-7901 cells (Supplementary Figure S2G). In previous studies, the Ras/Raf/MEK/ERK1/2 and PI3K signalling cascades were shown to play critical roles in the transmission of signals from growth factor receptors to regulate gene expression and prevent apoptosis [24, 25]. Our findings indicate that the combined effect of DT-13 and TPT leads to GC apoptosis via EGFR and its downstream signalling.…”

Section: Resultssupporting

confidence: 55%

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

Lin

Zhao

et al. 2016

Oncotarget

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Combination therapy has a higher success rate for many cancers compared to mono-therapy. The treatment of Topotecan (TPT) on gastric cancer (GC) is limited by its toxicity and the potential drug resistance. We found that the combination of the saponin monomer 13 from the dwarf lilyturf tuber (DT-13), performing anti-metastasis and anti-angiogenesis effects, with TPT synergistically induced apoptotic cytotoxicity in GCs with high EGF receptor (EGFR) expression, which was dependent on DT-13-induced endocytosis of EGFR. With TPT, DT-13 promoted EGFR ubiquitin--mediated degradation through myosin IIA-induced and Src/ caveolin-1 (Cav-1)-induced endocytosis of EGFR; inhibited EGFR downstream signalling and then increased the pro-apoptotic effects. Moreover, the synergistic pro-apoptotic efficacy of DT-13 and TPT in GCs with high EGFR expression was eliminated by both the NM II inhibitor (−)-blebbistatin and MYH-9 shRNA. The combination therapy of DT-13 with TPT showed stronger anti-tumour effects in vivo compared with their individual effects. Moreover, the results of combination therapy revealed selective upregulation of pro-apoptotic activity in TUNEL assays and cleaved caspase-3 and NM IIA in immunohischemical analysis; while specific downregulation of p-extracellular regulated kinase 1/2 (p-ERK1/2), EGFR and Cav-1 in immunohischemical analysis. Collectively, these findings have significant clinical implications for patients with tumours harbouring high EGFR expression due to the possible high sensitivity of this regimen.

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Section: Resultssupporting

confidence: 55%

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

Lin

Zhao

et al. 2016

Oncotarget

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“…70 The knockdown of Spred1 and Spred2 shows an effect similar to that of an MEK inhibitor and protects against apoptosis of BRAF V600E-positive melanoma cell lines. 71 The inhibition of the ERK pathway can even worsen the tumorigenesis of melanoma under certain conditions. Recently, biallelic inactivation mutations of Spred1 have been reported in patients with mucosal melanoma.…”

Section: Sprouty/spred and Melanomamentioning

confidence: 99%

The Sprouty/Spred family as tumor suppressors: Coming of age

Kawazoe

Taniguchi

2019

Cancer Science

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The Ras/Raf/ERK pathway is one of the most frequently dysregulated signaling pathways in various cancers. In some such cancers, Ras and Raf are hotspots for mutations, which cause continuous activation of this pathway. However, in some other cancers, it is known that negative regulators of the Ras/Raf/ERK pathway are responsible for uncontrolled activation. The Sprouty/Spred family is broadly recognized as important negative regulators of the Ras/Raf/ERK pathway, and its expression is downregulated in many malignancies, leading to hyperactivation of the Ras/Raf/ERK pathway. After the discovery of this family, intensive research investigated the mechanism by which it suppresses the Ras/Raf/ERK pathway and its roles in developmental and pathophysiological processes. In this review, we discuss the complicated roles of the Sprouty/Spred family in tumor initiation, promotion, and progression and its future therapeutic potential.

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“…Previous studies have demonstrated that the aberrant activation of MAPK pathway induces resistance to apoptosis in cancer cells [23,24]. Because miR-202 regulates the KRas/MAPK pathway, we decided to investigate the effect of miR-202 on cisplatin-induced apoptosis in NSCLC cells.…”

Section: Mir-202 Increases the Sensitivity Of Nsclc Cells To Cisplatimentioning

confidence: 99%

miR-202 Enhances the Anti-Tumor Effect of Cisplatin on Non-Small Cell Lung Cancer by Targeting the Ras/MAPK Pathway

Sun¹,

Wei²,

Tian³

et al. 2018

Cell Physiol Biochem

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Background/Aims: KRas is usually mutated in non-small cell lung cancer (NSCLC). The mutated KRas gene is a negative prognostic indicator that promotes tumor proliferation, metastasis, and drug resistance in NSCLC, and thus has become a target for cancer therapy. This study is focused on the effects of the microRNA (miR)-202/KRas axis in regulating chemosensitivity in NSCLC. Methods: Quantitative reverse transcriptase real-time PCR analysis was performed to examine the expression of miR-202. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays were performed to evaluate the sensitivity of cisplatin against NSCLC cells. The miR-202/KRas axis was confirmed by western blot and luciferase reporter assays. Cell apoptosis was measured by flow cytometry. KRas expression, MEK1/2 and ERK1/2 phosphorylation, and activation of caspase-9 and caspase-3 were detected by western blot. Results: A significant decrease in miR-202 expression was observed in NSCLC cells both in vivo and in vitro. In addition, miR-202 expression was associated with drug resistance. Recovery of miR-202 expression levels was found to increase the sensitivity of both NCI-H441 and A549 NSCLC cells to cisplatin treatment. Mechanically, as the Ras/mitogen-activated protein kinase (MAPK) pathway was aberrantly activated in NCI-H441 and A549 NSCLC cells, the overexpression of miR-202 was found to inhibit the Ras/MAPK pathway by targeting the KRas gene. As a result, increased miR-202 expression expanded apoptosis signaling induced by cisplatin in NSCLC cells. Conclusion: The miR-202/KRas axis controlled the chemosensitivity of NSCLC by mediating the Ras/MAPK pathway. Thus, the combination of platinum-based drugs with miR-202 may represent a novel strategy to enhance the anti-tumor effect against NSCLC.

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The MAPK pathway as an apoptosis enhancer in melanoma

Cited by 34 publications

References 57 publications

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo

The Sprouty/Spred family as tumor suppressors: Coming of age

miR-202 Enhances the Anti-Tumor Effect of Cisplatin on Non-Small Cell Lung Cancer by Targeting the Ras/MAPK Pathway

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