The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs

Fleisch, Markus; Maxwell, Christopher A.; Barcellos-Hoff, M. H.

doi:10.1677/erc.1.01112

Cited by 47 publications

(41 citation statements)

References 179 publications

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“…Cytokines are key mediators of inflammation that may relate to prostate cancer initiation and progression and that may be useful markers of prostatic neoplasias and related inflammation (63). TGF-h1, IL-6, and IL-8 act as survival factors inhibiting chemotherapy-induced apoptosis in androgen-independent PC-3 human prostate cancer cells (59,60).…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane Enhances the Therapeutic Potential of TRAIL in Prostate Cancer Orthotopic Model through Regulation of Apoptosis, Metastasis, and Angiogenesis

Shankar

Ganapathy

Srivastava

2008

Clinical Cancer Research

130

112

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Purpose: The purpose of this study was to examine the molecular mechanisms by which sulforaphane enhances the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer. Experimental Design: Cell viability and apoptosis assays were done by XTTand terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. Tumor-bearing mice were treated with vehicle, sulforaphane, TRAIL, and sulforaphane plus TRAIL. Markers of apoptosis, angiogenesis, and metastasis were measured by immunohistochemistry. Results: Sulforaphane enhanced the therapeutic potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Sulforaphane-induced apoptosis in PC-3 cells correlated with the generation of intracellular reactive oxygen species (ROS), collapse of mitochondrial membrane potential, activation of caspase-3 and caspase-9, and up-regulation of DR4 and DR5. Sulforaphane induced the expression of Bax, Bak, Bim, and Noxa and inhibited the expression of Bcl-2, Bcl-X L , and Mcl-1. The quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-induced ROS generation, mitochondrial membrane potential disruption, caspase-3 activation, and apoptosis. Sulforaphane inhibited growth of orthotopically implanted PC-3 tumors by inducing apoptosis and inhibiting proliferation and also enhanced the antitumor activity of TRAIL. Sulforaphane up-regulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and Bak and inhibited the activation of nuclear factor-nB P13K/AKTand MEK/ERK pathways in tumor tissues. The combination of sulforaphane and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis and activating FOXO3a transcription factor than single agent alone. Conclusions: The ability of sulforaphane to inhibit tumor growth, metastasis, and angiogenesis and to enhance the therapeutic potential of TRAIL suggests that sulforaphane alone or in combination withTRAIL can be used for the management of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Sulforaphane Enhances the Therapeutic Potential of TRAIL in Prostate Cancer Orthotopic Model through Regulation of Apoptosis, Metastasis, and Angiogenesis

Shankar

Ganapathy

Srivastava

2008

Clinical Cancer Research

130

112

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“…The combination of activin and betacellulin has also been shown to induce differentiation of the AR42J cells (Mashima et al, 1996). Activin binds to and activates the transforming growth factor-β (TGFβ) receptors (Fleisch et al, 2006). There are three mammalian forms of TGFβ, 1, 2, and 3, that can potentially bind three ubiquitously expressed TGFβ receptors, TβR I, II and III.…”

Section: In Vitro Determination Of the Mechanism Of β Cell Differentimentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

583

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…TGF-␤ is essential for growth control and development of the mammary gland (22,55). Interestingly, excessive ductal proliferation is seen in mice hemizygous for Tgf-␤1 or expressing a dominant-negative TGF-␤ type II receptor (20,21,28,29,41).…”

Section: ⌬L/⌬lmentioning

confidence: 99%

“…Strikingly, disruption of TGF-␤ signaling specifically in the mammary gland causes defects such as hyperplastic ductal epithelium and defective nursing (20,21,28,29,41). The relative importance of TGF-␤ growth inhibition compared to its other morphogenic signals in mammary gland development is unclear (22,77). However, many targets and components of TGF-␤'s cytostatic signaling cascade, such as cyclin D1 and p27, also participate in controlling mammary epithelial proliferation during development (25,27,48,59,80,81).…”

mentioning

confidence: 99%

A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

Francis¹,

Bergsied

Isaac³

et al. 2009

Molecular and Cellular Biology

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Transforming growth factor ␤ (TGF-␤) is a crucial mediator of breast development, and loss of TGF-␤-induced growth arrest is a hallmark of breast cancer. TGF-␤ has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-␤ cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1 ⌬L and Rb1 NF ), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-␤ growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-␤ signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-␤ cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-␤ in growth control and mammary gland development.

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The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs

Cited by 47 publications

References 179 publications

Sulforaphane Enhances the Therapeutic Potential of TRAIL in Prostate Cancer Orthotopic Model through Regulation of Apoptosis, Metastasis, and Angiogenesis

Sulforaphane Enhances the Therapeutic Potential of TRAIL in Prostate Cancer Orthotopic Model through Regulation of Apoptosis, Metastasis, and Angiogenesis

Mechanisms of action of glucagon-like peptide 1 in the pancreas

A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

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