Androgenic regulation of growth factor and growth factor receptor expression in the cwr22 model of prostatic adenocarcinoma

Myers, Richard S.; Oelschlager, Denise K.; Manne, Upender; Coan, Patricia N.; Weiss, Heidi L.; Grizzle, William E.

doi:10.1002/(sici)1097-0215(19990730)82:3<424::aid-ijc16>3.0.co;2-b

Cited by 32 publications

(30 citation statements)

References 24 publications

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“…The molecular mechanisms involved in the cooperative effects of bicalutamide and gefitinib appear to indicate an AR transactivation mediated by EGFR/HER2 signaling both through PI-3K-mediated Akt/PKB activation (since it may be blocked by 30 mg/ml LY294002) and through ERK-mediated AR phosphorylation (since it may be blocked by 10 mM PD98059). These results are in agreement with other experimental data obtained in CWR22 and CWR22R models 36,37 and with a recent study of ours. 24 In conclusion, our experiments suggest that combination therapy of anti-EGFR and nonstreroidal antiandrogen might block tumor cell growth and that it is possible to raise the maximal effect in the combination of bicalutamide with low doses of gefitinib.…”

Section: Discussionsupporting

confidence: 94%

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Festuccia

Gravina

Angelucci

et al. 2005

Intl Journal of Cancer

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Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR-positive cells (LNCaP, CWR22, CWR22R 2152 and AR-transfected DU145 cell lines) compared with AR-negative cells (DU145, PC3 and TSUPr1). Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells. All AR-positive PCa cell lines were sensitive to gefitinib (IC 50 = 0.1-0.6 mM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC 50 = 0.8-2.0 mM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC 50 of bicalutamide (approximately 10-fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC 50 of gefitinib (approximately 5-fold). Taken together, our data suggest that in androgen-dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFRdriven androgen independence. ' 2005 Wiley-Liss, Inc. Key words: prostate cancer; hormonal therapy; EGFR; androgenindependent tumorsIn industrialized countries, prostate cancer (PCa) is the most frequently occurring malignancy in men, representing the second highest cause of cancer-related death. PCa usually begins as an androgen-sensitive, androgen-dependent (AD), nonmetastatic cancer, which without intervention may follow a gradual transition into a highly metastatic and then androgen-insensitive (AI) variety. The androgen receptor (AR) is a nuclear receptor that cooperates with multiple proteins to exert its biologic function. Upon binding to the ligand testosterone/5 -dihydrotestosterone (DHT), the AR can bind to the androgen response element (ARE) on the 5 0 promoter of target genes, resulting in the modulation of cell growth. Until relatively recent times, endocrine response pathways in PCa were described solely in terms of the intracellular pathways used by the androgens and the subsequent destructive effects exerted on AR signaling by antihormonal treatments. 1 It is widely accepted that androgens promote tumor growth by binding to ARs and acting as nuclear transcription factors that regulate the expression of genes involved in cell proliferation and survival mechanisms. In contrast, hormonal therapies promote tumor regression either by reducing the amount of androgens available to the tumor cells or...

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Section: Discussionsupporting

confidence: 94%

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Festuccia

Gravina

Angelucci

et al. 2005

Intl Journal of Cancer

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“…Recurrent growth of the androgen-dependent CWR22 xenograft in the absence of testis-derived androgen occurred in the presence of increased expression of TGF␣, which could establish an autocrine regulatory loop through the EGF receptor (87). Recurrent CWR22 tumors express high levels of EGF-related ligands compared with the androgen-dependent tumor (94), and increased immunostaining of TGF␣ was found in recurrent CWR22 xenografts (87). Further support for an autocrine regulatory loop comes from observations that CWR-R1 cells express EGF, heparin-binding EGF, TGF␣, and heregulin messenger RNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, increased signaling by EGF and TGF␣ was reported to occur in association with the transition from androgen-dependent to recurrent prostate cancer (87), and prostate cancer cell lines have been shown to synthesize and secrete EGF and related peptides (88). In addition, the EGF family of receptors is expressed in most recurrent prostate cancers (89), with ErbB2 protein expression most frequently reported (90 -93).…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Increases Coactivation of the Androgen Receptor in Recurrent Prostate Cancer

Gregory

Fei

Ponguta

et al. 2004

Journal of Biological Chemistry

195

170

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Growth of normal and neoplastic prostate is mediated by the androgen receptor (AR), a ligand-dependent transcription factor activated by high affinity androgen binding. The AR is highly expressed in recurrent prostate cancer cells that proliferate despite reduced circulating androgen. In this report, we show that epidermal growth factor (EGF) increases androgen-dependent AR transactivation in the recurrent prostate cancer cell line CWR-R1 through a mechanism that involves a posttranscriptional increase in the p160 coactivator transcriptional intermediary factor 2/glucocorticoid receptor interacting protein 1 (TIF2/GRIP1). Site-specific mutagenesis and selective MAPK inhibitors linked the EGF-induced increase in AR transactivation to phosphorylation of TIF2/GRIP1. EGF signaling increased the coimmunoprecipitation of TIF2 and AR. AR transactivation and its stimulation by EGF were reduced by small interfering RNA inhibition of TIF2/GRIP1 expression. The data indicate that EGF signaling through MAPK increases TIF2/GRIP1 coactivation of AR transactivation in recurrent prostate cancer.

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“…8 Activated EGFR pathways are considered to belong to mechanisms that take over on development of androgen resistance. [42][43][44] Similarly, the IL-6 pathway has been suggested to play an important role in the development and growth of androgen-independent prostate cancer. 45 As shown before by others, [46][47][48] we also found that a short-term treatment with IL-6 inhibits growth of androgen-responsive LNCaP cells, whereas in androgen-unresponsive PC3 cells it evokes a growth stimulatory effect.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical detection of tyrosine phosphatase SHP‐1 predicts outcome after radical prostatectomy for localized prostate cancer

Tassidis

Brokken

Jirström

et al. 2010

Intl Journal of Cancer

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The protein tyrosine kinase (PTK) receptors and cytosolic signaling proteins as well as the protein tyrosine phosphatases (PTPs) have important roles in regulation of growth of the benign and malignant prostate gland. Here, we studied expression of the protein tyrosine phosphatase SHP-1 in prostate cancer cell lines and in human prostatic tissues. SHP-1 is expressed at a high level in LNCaP prostate cancer cells compared with PC3 cells. Silencing of SHP-1 expression with siRNA in LNCaP cells led to an increased rate of proliferation, whereas overexpression of SHP-1 by means of transient and stable transfection in PC3 cells led to a decrease in proliferation. Corresponding changes were observed in cyclin D1 expression. We further demonstrate that LNCaP and PC3 cells respond differently to IL-6 stimulation. SHP-1 overexpression in PC3 cells reversed IL-6 stimulation of proliferation, whereas in SHP-1-silenced LNCaP cells, IL-6 inhibition of proliferation was not affected. In addition, IL-6 treatment led to higher levels of phosphorylated STAT3 in SHP-1-silenced LNCaP cells than in control cells. Next, SHP-1 expression in human prostate cancer was analyzed by immunohistochemical staining of tissue microarrays comprising tumor specimens from 100 prostate cancer patients. We found an inverse correlation between the tumor level of SHP-1 expression and time to biochemical recurrence and clinical progression among prostate cancer patients. In conclusion, our results suggest that a decreased level of SHP-1 expression in prostate cancer cells is associated with a high proliferation rate and an increased risk of recurrence or clinical progression after radical prostatectomy for localized prostate cancer.

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Androgenic regulation of growth factor and growth factor receptor expression in the cwr22 model of prostatic adenocarcinoma

Cited by 32 publications

References 24 publications

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Retracted: Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro

Epidermal Growth Factor Increases Coactivation of the Androgen Receptor in Recurrent Prostate Cancer

Immunohistochemical detection of tyrosine phosphatase SHP‐1 predicts outcome after radical prostatectomy for localized prostate cancer

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