Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-α in human prostate cancer cells

Seth, Daya S.; Shaw, Kathryn; Jazayeri, Jalal; Leedman, Peter J.

doi:10.1038/sj.bjc.6690407

Cited by 68 publications

(39 citation statements)

References 54 publications

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“…TGF-α is one of the two EGFR ligands expressed in prostate cancer. Previous studies have demonstrated that with the disease progresses to more advanced stages, TGF-α is the predominant ligand for EGFR (33,34). Moreover, cell lines derived from different prostatic cancers and their metastases, including DU145 overexpress TGF-α (35,36), and TGF-α/EGFR autocrine loop is a hallmark of PCa invasion and progression (37,38).…”

Section: Discussionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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Abstract. ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE), is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines. Although aberrant expression of ADAM17 has been shown in various malignancies, the function of ADAM17 in prostate cancer has not been clarified. In the present study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell invasion, as well as the mechanism involved in the process. The expression pattern of ADAM17 was investigated in human prostate cancer cells. The results showed that ADAM17 expression levels are correlated with the invasive ability of androgen-independent prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation of MMP-2, MMP-9, and an increased TGF-α release into the supernatant. However, AG1478, PD98059 and antibody against TGF-α deactivating the EGFR-MEK-ERK signaling pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion. In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability, deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-α released and down-regulation of MMP-2, MMP-9. However, these effects could be reversed by simultaneous addition of TGF-α. These data demonstrated that ADAM17 contributes to androgen-independent prostate cancer cell invasion by shedding of EGFR ligand TGF-α, which subsequently activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be a new predictive biomarker of invasion and metastasis of prostate cancer, and ADAM17 could provide a target for treating metastatic PCa. IntroductionProstate cancer (PCa) is one of the most common malignancies among Western males with an occurrence of approximately 192,280 new cases and 27,360 deaths in the US, in 2009 (1). The growth and maintenance of cancerous cells in the early stages of prostate cancer is androgen-dependent and therapy often involves androgen deprivation (2). In the later stages therapeutic alternatives are not available, as the tumor progresses from androgen-dependence to -independence. The lack of effective therapies for advanced PCa is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Therefore, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of PCa (4).The ADAMs (a disintegrin and metalloproteinase) are members of the metzincin superfamily of Zn-dependent matrix metalloproteinases. They are transmembrane and secreted proteins with important roles in diverse biological functions, such as fertilization, adhesion, migration, proteolysis and signaling (5,6). Recent...

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Section: Discussionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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“…In colon cancer cell lines amphiregulin acts as a potent autocrine factor (Damstrup et al 1999). TGFα is the most prominent EGFR ligand which is frequently co-expressed with the EGFR in non-small-cell lung cancers (Hsieh et al 2000), prostate cancer (Seth et al 1999) and gastrointestinal stromal tumours (Cai et al 1999). In human mammary epithelial cells the critical contribution of metalloproteases in generating biologically active TGFα could be shown since batimastat, a metalloprotease inhibitor, is able to inhibit cell proliferation and migration (Dong et al 1999).…”

Section: Autocrine Growth Factor Loopsmentioning

confidence: 99%

The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.

Prenzel¹,

Fischer²,

Streit³

et al. 2001

Endocrine-Related Cancer

595

471

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Homeostasis of multicellular organisms is critically dependent on the correct interpretation of the plethora of signals which cells are exposed to during their lifespan. Various soluble factors regulate the activation state of cellular receptors which are coupled to a complex signal transduction network that ultimately generates signals defining the required biological response. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases represents both key regulators of normal cellular development as well as critical players in a variety of pathophysiological phenomena. The aim of this review is to give a broad overview of signal transduction networks that are controlled by the EGFR superfamily of receptors in health and disease and its application for target-selective therapeutic intervention. Since the EGFR and HER2 were recently identified as critical players in the transduction of signals by a variety of cell surface receptors, such as G-protein-coupled receptors and integrins, our special focus is the mechanisms and significance of the interconnectivity between heterologous signalling systems.

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“…The most prominent ligand, which is involved in autocrine growth receptor activation, is TGFα (Seth et al 1999, Hsieh et al 2000. Coexpression of TGFα and EGFR is frequently observed in glioblastomas and squamous cell carcinomas of the head and neck where it is correlated with poor prognosis (Grandis et al 1998).…”

Section: Egfrmentioning

confidence: 99%

Receptor tyrosine kinase signalling as a target for cancer intervention strategies.

Zwick¹,

Bange²,

Ullrich

2001

Endocrine-Related Cancer

346

217

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In multicellular organisms, communication between individual cells is essential for the regulation and coordination of complex cellular processes such as growth, differentiation, migration and apoptosis. The plethora of signal transduction networks mediating these biological processes is regulated in part by polypeptide growth factors that can generate signals by activating cell surface receptors either in paracrine or autocrine manner. The primary mediators of such physiological cell responses are receptor tyrosine kinases (RTKs) that couple ligand binding to downstream signalling cascades and gene transcription. Investigations over the past 18 years have revealed that RTKs are not only key regulators of normal cellular processes but are also critically involved in the development and progression of human cancers. Therefore, signalling pathways controlled by tyrosine kinases offer unique opportunities for pharmacological intervention. The aim of this review is to give a broad overview of RTK signalling involved in tumorigenesis and the possibility of target-selective intervention for anti-cancer therapy.

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Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-α in human prostate cancer cells

Cited by 68 publications

References 54 publications

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.

Receptor tyrosine kinase signalling as a target for cancer intervention strategies.

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