Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

Roberts, Patrick; Der, Channing J.

doi:10.1038/sj.onc.1210422

Cited by 2,445 publications

(2,035 citation statements)

References 139 publications

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“…In addition to cell cycle checkpoint signalling, mitogen-activated protein kinase (MAPK) cascades are critical signalling pathways and well-known proto-oncogenes which regulate cell proliferation, survival and differentiation of both normal and malignant cells (Roberts and Der, 2007). Hence, it is not surprising that aberrant regulation of MAPK cascades contribute to cancer and other human diseases.…”

Section: Future Workmentioning

confidence: 99%

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

2014

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Section: Future Workmentioning

confidence: 99%

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

2014

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“…Because the Ras-Raf-MEK-ERK pathway is one of the most frequently activated oncogenic pathway in human cancers, this signaling pathway has been subjected to intensive research to identify novel inhibitors for cancer treatment. Among them, BAY 43-9006 (Raf inhibitor), PD184352, PD0325901 and ARRY-142886 (MEK1/2 inhibitors) have reached the clinical trial stage (Roberts and Der, 2007). Intriguingly, no inhibitors of ERK1 or ERK2 have been described so far.…”

Section: Perspectivesmentioning

confidence: 99%

MAPK signaling in inflammation-associated cancer development

2010

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Mitogen-activated protein (MAP) kinases comprise a family of protein-serine/threonine kinases, which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms, including mammals. These kinases, including ERKs, JNKs and p38s, are regulated by a phosphorelay cascade, with a prototype of three protein kinases that sequentially phosphorylate one another. MAPKs transduce extracellular signals into a variety of cellular processes, such as cell proliferation, survival, death, and differentiation. Consistent with their essential cellular functions, MAPKs have been shown to play critical roles in embryonic development, adult tissue homeostasis and various pathologies. In this review, we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and, particularly, inflammation-associated cancer development.

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“…In the present study, suppression of the pathways of p44/42 and p38 MAPKs, pAkt and p-NF-jB by bufalin could be responsible for the reduction of COX-2 expression in A549 cells. The ERK1/2 and p38 MAPK signaling pathways can be activated in response to a diverse range of extracellular stimuli including mitogens, growth factors, and cytokines (Baccarini 2005;Meloche and Pouysségur 2007;Roux and Blenis 2004) and are important targets in the diagnosis and treatment of cancer (Roberts and Der 2007). Suppression of the activated EGFR and ERK1/2 and p38 MAPKs as well as Akt signaling pathways led to inhibition of the proliferation of A549 cells (Baldys et al 2007;Nguyen et al 2004;Recchia et al 2009;Su et al 2010).…”

Section: Bufalin Reduces the Receptor Phosphorylation And/or Proteinmentioning

confidence: 99%

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

et al. 2010

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Bufalin, a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Chansu showed inhibitory effects against human prostate, hepatocellular, endometrial and ovarian cancer cells, and leukemia cells. However, whether or not bufalin has inhibitory activity against the proliferation of human non-small cell lung cancer (NSCLC) cells is unclear. The aim of this study is to study the effects of bufalin on the proliferation of NSCLC and its molecular mechanisms of action. The cancer cell proliferation was measured by MTT assay. The apoptosis and cell cycle distribution were analyzed by flow cytometry. The protein expressions and phosphorylation in the cancer cells were detected by Western blot analysis. In the present study, we have demonstrated that bufalin suppressed the proliferation of human NSCLC A549 cell line in time-and dosedependent manners. Bufalin induced the apoptosis and cell cycle arrest by affecting the protein expressions of Bcl-2/Bax, cytochrome c, caspase-3, PARP, p53, p21WAF1, cyclinD1, and COX-2 in A549 cells. In addition, bufalin reduced the protein levels of receptor expressions and/or phosphorylation of VEGFR1, VEGFR2, EGFR and/or c-Met in A549 cells. Furthermore, bufalin inhibited the protein expressions and phosphorylation of Akt, NF-jB, p44/42 MAPK (ERK1/2) and p38 MAPK in A549 cells. Our results suggest that bufalin inhibits the human lung cancer cell proliferation via VEGFR1/VEGFR2/EGFR/cMet-Akt/p44/42/p38-NF-jB signaling pathways; bufalin may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of human NSCLC.

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Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

Cited by 2,445 publications

References 139 publications

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

MAPK signaling in inflammation-associated cancer development

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

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