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, Adam; Sebti, Saı̈d M.

doi:10.1038/sj.onc.1210172

Cited by 65 publications

(80 citation statements)

References 45 publications

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“…Carie and Sebti demonstrated that inhibition of the Raf-1/ Mek-1/ERK1/2 pathway by a β-AR agonist can result in growth inhibition of MDA-MB-231 breast cancer cells in vivo [26] . Shin et al reported that the catecholamines stimulate β2-AR while carcinogens like nicotine can interact with β2-AR to activate the downstream protein kinase C/ERK1/2/ cyclooxygenase 2 pathway, leading to the proliferation of gas- [27] .…”

Section: Discussionmentioning

confidence: 99%

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Qing

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim: To examine whether β-adrenoceptor (β-AR) agonists can induce hypoxia-inducible factor (HIF)-1α accumulation which then upregulate the expression of its target genes in pancreatic cancer cells at normoxia, and to further elucidate the mechanism involved. Methods: Pulse-chase assay, RT-PCR, and Western blot were employed to detect the effects of β-AR agonists and antagonists, siRNA as well as several inhibitors of signal transduction pathways on MIA PaCa2 and BxPC-3 pancreatic cancer cells. Results: Treatment of pancreatic cancer cell lines with β-AR agonists led to accumulation of HIF-1α and then up-regulated expression of its target genes independently of oxygen levels. The induction was partly or completely inhibited not only by β-AR antagonists but also by inhibitors of PKA transduction pathways and by siHIF-1α. Both β1-AR and β2-AR agonists produced the above-mentioned effects, but β2-AR agonist was more potent. Conclusion: Activation of β-AR receptor transactivates epidermal growth factor receptor (EGFR) and then elicites Akt and ERK1/2 in a PKA-dependent manner, which together up-regulate levels of HIF-1α and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links β-AR and HIF-1α signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.

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Section: Discussionmentioning

confidence: 99%

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Qing

Zhang

et al. 2009

Acta Pharmacol Sin

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“…A549 or H1650 cells were harvested and resuspended in PBS and implanted s.c. into the right and left flanks (10 Â 10 6 cells per flank) of 8-wk-old female athymic nude mice (Charles River) as described (18,23). When tumors reached f100 to 200 mm with ABC kit from Vector Laboratories, rinsed in dH 2 O, and developed with 3,3 ¶-diaminobenzidine.…”

Section: Methodsmentioning

confidence: 99%

A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice

et al. 2008

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Although it is well established that cyclin-dependent kinases phosphorylate and inactivate Rb, the Raf-1 kinase physically interacts with Rb and initiates the phosphorylation cascade early in the cell cycle. We have identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251), that potently and selectively disrupts the Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E, and Rb/HDAC binding. The selective inhibition of Rb/Raf-1 binding suppressed the ability of Rb to recruit Raf-1 to proliferative promoters and inhibited E2F1-dependent transcriptional activity. RRD-251 inhibited anchorage-dependent and anchorage-independent growth of human cancer cells and knockdown of Rb with short hairpin RNA or forced expression of E2F1 rescued cells from RRD-251-mediated growth arrest. P.o. treatment of mice resulted in significant tumor growth suppression only in tumors with functional Rb, and this was accompanied by inhibition of angiogenesis, inhibition of proliferation, decreased phosphorylated Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents. [Cancer Res 2008;68(10):3810-8]

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“…In contrast, Carie and Sebti have demonstrated that ADRB2 agonist pirbuterol causes human tumor regression in MDA-MB-231 breast cancer in vivo by blocking the Raf-1/Mek-1/Erk1/2 pathway. However, the authors acknowledge that this approach is limited to human cancers that not only express ADRB2, but also that stimulation of this receptor results in the blockade of the Raf-1/Mek-1/Erk 1/2 pathway [27]. In addition to the stimulation by catecholamines on ADRB2, carcinogens like nicotine may interact with ADRB2 and the downstream protein kinase C/Erk1/2/cyclooxygenase 2 pathway to lead to cell proliferation of gastric cancer cells [28].…”

Section: Proliferation and Growth Of Primary Tumor And Metastasesmentioning

confidence: 99%

Neuroendocrine influences on cancer biology

Thaker

Sood

2008

Seminars in Cancer Biology

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Over the past 25 years, epidemiological and clinical studies have linked psychological factors such as stress, chronic depression, and lack of social support to the incidence and progression of cancer [1,2]. Although the mechanisms underlying these observations are not completely understood, recent molecular and animal studies have begun to identify specific signaling pathways that could explain the impact of neuroendocrine effects on tumor growth and metastasis. This review will highlight the importance of known clinical, molecular, and cellular processes with regard to the neuroendocrine stress effects on tumor biology and discuss possible behavioral and pharmacological interventions to ameliorate these effects and ultimately improve cancer outcomes.

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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

Cited by 65 publications

References 45 publications

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

A Small Molecule Disruptor of Rb/Raf-1 Interaction Inhibits Cell Proliferation, Angiogenesis, and Growth of Human Tumor Xenografts in Nude Mice

Neuroendocrine influences on cancer biology

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