Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo

Sebolt-Leopold, Judy; Dudley, David T.; Herrera, Román; Becelaere, Keri Van; Wiland, Anne; Gowan, Richard; Tecle, Haile; Barrett, Stephen D.; Bridges, Alex J.; Przybranowski, Sally; Leopold, Wilbur R.; Saltiel, Alan R.

doi:10.1038/10533

Cited by 909 publications

(682 citation statements)

References 35 publications

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“…This conclusion is supported by a recent publication showing that a blockade in the MAPK pathway by a selective inhibitor of MEK prevents the growth of colon carcinomas in mice, and further demonstrating that cellular proliferation strongly requires an active MEK/ERK pathway (Sebolt-Leopold et al, 1999).…”

Section: Discussionmentioning

confidence: 57%

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

2000

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Summary Interferon (IFN)-α affects the growth, differentiation and function of various cell types by transducing regulatory signals through the Janus tyrosine kinase/signal transducers of activation and transcription (Jak/STAT) pathway. The signalling pathways employing the mitogenactivated ERK-activating kinase (MEK) and the extracellular-regulated kinase (ERK) are critical in growth factors signalling. Engagement of the receptors, and subsequent stimulation of Ras and Raf, initiates a phosphorylative cascade leading to activation of several proteins among which MEK and ERK play a central role in routing signals critical in controlling cell development, activation and proliferation. We demonstrate here that 24-48 h following treatment of transformed T-and monocytoid cell lines with recombinant human IFN-α2b both the phosphorylation and activity of MEK1 and its substrates ERK1/2 were reduced. In contrast, the activities of the upstream molecules Ras and Raf-1 were not affected. No effect on MEK/ERK activity was observed upon short-term exposure (1-30 min) to IFN. The anti-proliferative effect of IFN-α was increased by the addition in the culture medium of a specific inhibitor of MEK, namely PD98059. In conclusion, our results indicate that IFN-α regulates the activity of the MEK/ERK pathway and consequently modulates cellular proliferation through a Ras/Raf-independent mechanism. Targeting the MEK/ERK pathway may strengthen the IFN-mediated anti-cancer effect.

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Section: Discussionmentioning

confidence: 57%

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

2000

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“…(Di Marco et al, 1989;Fleming et al, 1992;Watanabe et al, 1996;Graells et al, 2004). More importantly, hyperactivation of this pathway is critical to the growth and survival of human tumors (Sebolt-Leopold et al, 1999). Finally, thwarting this pathway in human cancers may result in great benefits in the treatment of cancer ARA-211 suppresses P-Erk1/2 levels, inhibits tumor cell growth and induces apoptosis in human xenografts in nude mice.…”

Section: Discussionmentioning

confidence: 99%

“…Not only have these oncogenic and tumor survival pathways been found constitutively activated in the great majority of human cancers, but also their hyperactivation has been associated with poor prognosis and resistance to chemotherapy in cancer patients (Slamon et al, 1987). This has prompted drug discovery efforts targeting receptor tyrosine kinases, Ras, Raf-1, Mek, Akt and STAT3 to thwart aberrant signal transduction pathways in tumor cells (Sebolt-Leopold et al, 1999;Sebolt-Leopold, 2000;Weinstein-Oppenheimer et al, 2000;Blaskovich et al, 2003;Redell and Tweardy, 2005). For example, inhibitors of receptor tyrosine kinases, Ras, Raf-1 and Mek-1 have all been identified and are at various stages of development (English and Cobb, 2002;Hao and Rowinsky, 2002).…”

Section: Introductionmentioning

confidence: 99%

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

Carie

Sebti

2007

Oncogene

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A chemical biology approach identifies a beta 2 adrenergic receptor (b2AR) agonist ARA-211 (Pirbuterol), which causes apoptosis and human tumor regression in animal models. b2AR stimulation of cAMP formation and protein kinase A (PKA) activation leads to Raf-1 (but not B-Raf) kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-extracellular signal-regulated kinase (Erk)1/2 levels. ARA-211 inhibition of the Raf/ Mek/Erk1/2 pathway is mediated by PKA and not exchange protein activated by cAMP (EPAC). ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. b2AR stimulation results in inhibition of anchorage-dependent and -independent growth, induction of apoptosis in vitro and tumor regression in vivo. b2AR antagonists and constitutively active Mek-1 rescue from the effects of ARA-211, demonstrating that b2AR stimulation and Mek kinase inhibition are required for ARA-211 antitumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, b2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway by a cAMP-dependent activation of PKA but not EPAC.

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“…In a recent breakthrough in this field, a highly potent inhibitor of MAP kinase activation has been identified which is capable of inhibiting human cancer growth in immunedeficient mice (Sebolt-Leopold et al, 1999). We have recently demonstrated a direct physical interaction between avb6 and a member of the MAP kinase family, extracellular signal-regulated kinase 2 (ERK2) which defines a novel paradigm of integrinmediated signalling in cancer (Ahmed et al, 2002).…”

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confidence: 99%

Integrin αvβ6-associated ERK2 mediates MMP-9 secretion in colon cancer cells

Dorahy

et al. 2002

Br J Cancer

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There is general consensus that matrix metalloproteinases are involved in tumour progression. We show herein that inhibition of integrin avb6 expression in colon cancer cells suppresses MMP-9 secretion. This integrin-mediated event is dependent upon direct binding between the b6 integrin subunit and extracellular signal-regulated kinase 2. Targetting either b6 or its interaction with extracellular signal-regulated kinase in order to inhibit matrix metalloproteinase activity may offer a useful therapeutic approach in preventing growth and spread of colon cancer.

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Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo

Cited by 909 publications

References 35 publications

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

Integrin αvβ6-associated ERK2 mediates MMP-9 secretion in colon cancer cells

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