The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors?

Kunnimalaiyaan, Muthusamy; Chen, Herbert

doi:10.1097/00001813-200602000-00004

Cited by 39 publications

(36 citation statements)

References 33 publications

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“…MTC accounts for 3% to 5% of all thyroid cancers and originates from the C cells of the thyroid (16,20,33). MTC tends to be a slow-growing tumor, but the primary therapy for patients with MTC is surgical resection.…”

Section: Discussionmentioning

confidence: 99%

“…This emphasizes the need for the development of new treatment strategies. Several signaling pathways such as the phosphoinositide-3-kinase (PI3K)/Akt pathway and the raf-1/mitogen-regulated extracellular kinase (MEK)/ extracellular regulated kinase (ERK) pathway have been shown to play an important role in regulating tumor cell growth (16). The raf-1/MEK/ERK pathway has long been recognized for its importance in cancer biology.…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of glycogen synthase kinase-3β, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells

Kunnimalaiyaan

Vaccaro

Ndiaye

et al. 2007

Molecular Cancer Therapeutics

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109

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Glycogen synthase kinase-3B (GSK-3B) is an important regulator of cell proliferation and survival. Conflicting observations have been reported regarding the regulation of GSK-3B and extracellular signal -regulated kinase (ERK1/2) in cancer cells. In this study, we found that raf-1 activation in human medullary thyroid cancer cells, TT cells, resulted in phosphorylation of GSK-3B. Inactivation of GSK-3B in TT cells with well-known GSK-3B inhibitors such as lithium chloride (LiCl) and SB216763 is associated with both growth suppression and a significant decrease in neuroendocrine markers such as human achaete-scute complex-like 1 and chromogranin A. Growth inhibition by GSK-3B inactivation was found to be associated with cell cycle arrest due to an increase in the levels of cyclin-dependent kinase inhibitors such as p21, p27, and p15. Additionally, LiCl-treated TT xenograft mice had a significant reduction in tumor volume compared with those treated with control. For the first time, we show that GSK-3B is a key downstream target of the raf-1 pathway in TT cells. Also, our results show that inactivation of GSK-3B alone is sufficient to inhibit the growth of TT cells both in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inactivation of glycogen synthase kinase-3β, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells

Kunnimalaiyaan

Vaccaro

Ndiaye

et al. 2007

Molecular Cancer Therapeutics

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109

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“…Lung cancer by itself accounts for more deaths than colorectal, breast, and prostate cancers combined (4). SCLC is the most aggressive type of lung cancer, and is characterized by rapid spread to regional lymph nodes as well as other distant sites of metastasis (3)(4)(5)(6)(7)(8).…”

Section: Discussionmentioning

confidence: 99%

“…In 2007, an estimated 213,380 Americans will be diagnosed with lung cancer and 160,390 will die of the disease (1). Small cell lung cancer (SCLC) accounts for approximately 20% of all lung cancer cases (3)(4)(5)(6) and is characterized by an aggressive course with early metastasis (3)(4)(5)(6)(7)(8). Without treatment, the median survival time with the disease is only 2-3 months (3).…”

Section: Introductionmentioning

confidence: 99%

Valproic Acid Induces Notch1 Signaling in Small Cell Lung Cancer Cells

Platta

Greenblatt

Kunnimalaiyaan

et al. 2008

Journal of Surgical Research

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Background-Small cell lung cancer (SCLC) is an aggressive malignancy. Current treatments yield dismal survival rates. We have previously demonstrated that histone deacetylase (HDAC) inhibitors can inhibit neuroendocrine tumor growth. Activation of the Notch1 signaling pathway also impairs SCLC cell viability. In this study, we investigated the ability of the HDAC inhibitor valproic acid (VPA) to activate Notch1 signaling and inhibit proliferation in SCLC cells.

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“…Sustained Raf-1 activation in MTC cells leads to reduction in ASCL1, CgA, and consequently cell growth arrest [8]. Mitogenactivated protein kinases (MAPKs) represent the largest family of protein kinases that control cellular proliferation, cell differentiation and apoptosis by regulating diverse intracellular signal transduction cascades.…”

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confidence: 99%

Activation of Mek Alters Morphology and Neuroendocrine Phenotype in Medullary Thyroid Cancer Cell

Alhefdhi¹,

Kunnimalaiyaan²,

Chen³

2016

EMIJ

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SynopsisActivation of the MEK pathway in MTC cells elicited similar effects of raf-1 pathway activation, resulting in cell growth suppression. Therefore, MEK may serve as a molecular target and a therapeutic strategy to treat patients with MTC. IntroductionMedullary thyroid cancer (MTC) is a neuroendocrine (NE) tumor that arises from the parafollicular cells (C-cells) of the thyroid gland [1]. MTC accounts for 5-10% of all thyroid malignancies and responds poorly to chemotherapy [2]. Thus, the only curative option for MTC is surgical resection [1]. MTC is the end result of an oncogenic activation of protein cascades in the NE cells of the thyroid gland [3]. Hence, understanding the molecular pathways that control C-cell proliferation is vital for developing novel therapies for patients with advanced MTC [4].MTC cells produce several hormones and NE markers such as calcitonin, Chromogranin A (CgA) [5], and Achaete Scute Complex-Like 1 (ASCL1), also known as human ASH1 (Achaete Scute Homolog-1) [6,7]. ASCL1 is involved in C-cell expansion and is critical for neuroendocrine cell differentiation and MTC tumor growth. The importance of ASCL1 for C-cell growth was observed in transgenic mice with an ASCL1 knockout gene, which failed to develop thyroid C-cells [1]. Moreover, ASCL1 has been found to be involved in the development of other NE cells such as pulmonary endocrine cells and chromaffin cells [1]. AbstractBackground: Medullary thyroid cancer (MTC) is a neuroendocrine (NE) tumor of the thyroid C cells. Surgery is the only curative therapy. Activation of raf-1 in MTC cells resulted in growth suppression and NE marker reduction. However, the exact mediator of this effect is not clearly understood. We hypothesize that MEK, a key downstream target of raf-1 pathway, may be involved in the effect seen with raf-1 activation in MTC. To determine the role of MEK, we established a doxycyclineinducible MEK in MTC TT cells and assessed the effects on morphology and NE phenotype.Methods: Doxycycline-inducible TT-MEK cells were created by stable transfection of a pRevTRE-MEK plasmid in TT cells expressing a Tet responsive protein. TT-MEK cells were treated with 0-1.0μg/ml of doxycycline for four days. The level of total and active MEK expression was determined by western blot analysis using MEK and phosphorylated ERK1/2 antibodies. In addition, the lysates were analyzed for levels of the NE markers achaete-scute complex like 1 (ASCL1) and Chromogranin A (CgA). Morphology of the treated and control cells was observed under a light microscope.Results: Treatment of TT-MEK cells with doxycycline led to an induction of MEK protein, which is associated with activation of ERK1/2 in a dose-dependent manner. Importantly, the levels of NE markers were reduced by increasing MEK activation. Similar to RAF-1 activation, there was a striking morphological change with activation of MEK1/2, with a decrease in horizontal spread of each cell resulting in rounder, larger cells. Conclusion:We demonstrate, for the first time, that the over exp...

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The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors?

Cited by 39 publications

References 33 publications

Inactivation of glycogen synthase kinase-3β, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells

Inactivation of glycogen synthase kinase-3β, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells

Valproic Acid Induces Notch1 Signaling in Small Cell Lung Cancer Cells

Activation of Mek Alters Morphology and Neuroendocrine Phenotype in Medullary Thyroid Cancer Cell

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