ErbB1 and prostate cancer: ErbB1 activity is essential for androgen‐induced proliferation and protection from the apoptotic effects of LY294002

Tørring, Niels; Dagnæs‐Hansen, Frederik; Sørensen, Boe Sandahl; Nexø, Ebba; Hynes, Nancy E.

doi:10.1002/pros.10245

Cited by 42 publications

(43 citation statements)

References 27 publications

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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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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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show abstract

“…Activated EGFR may induce distinct mitotic cascades, including the MAPK, PI3K/Akt, Shc, NF-κB and phospholipase Cg signalling pathways, which stimulate the proliferation, survival, motility and invasiveness of prostate cancer cells [29][30][31][32]. Elevated Akt activity may have a profound role in the progression of human prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

Xia¹,

Luo²,

Wang³

2009

Asian J Androl

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Abstractp27 is a cyclin-dependent kinase inhibitor that regulates the progression of cells from G 1 to S phase of the cell cycle. Loss of p27 has been associated with disease progression and with an unfavourable outcome in prostate cancer. In this study, we investigated whether exogenous p27 expression in the human androgen-independent prostate cancer PC3 cell line had any effect on cell growth, and we studied the molecular mechanisms involved. p27 expression was restored in PC3 cells by plasmid delivery. Cell proliferation and apoptosis were assessed in PC3 cells transfected with p27. We also investigated the effects of p27 on the epidermal growth factor receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway in PC3 cells. By restoring p27 expression in PC3 cells, we observed that p27 reduced proliferation and induced arrest in G 0 /G 1 phase. Moreover, p27-transfected PC3 cells underwent apoptosis, as shown by flow cytometric analysis and western blotting analysis of Bcl-2, Bax, Bad, caspase-3 and poly(ADP-ribose)polymerase expression. Furthermore, the p27-induced anti-tumour action correlated with inhibition of the EGFR/PI3K/Akt signalling pathway, as confirmed by western blotting analysis and densitometry of EGFR, PI3K (p85), Akt and p-Akt S473 expression. Our results suggest that exogenous expression of p27 inhibits the proliferation of PC3 cells through induction of G 1 arrest and apoptosis, and this process correlates with inhibition of the EGFR/PI3K/Akt signalling pathway.

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“…Several groups have demonstrated the role of increased EGFR signaling in prostate carcinogenesis and progression (Sherwood et al, 1998;Ratan et al, 2003;Torring et al, 2003). We have recently reported the discovery of four somatic missense mutations in the tyrosine kinase domain of EGFR in prostate cancer patients (Douglas et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

et al. 2008

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While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.

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ErbB1 and prostate cancer: ErbB1 activity is essential for androgen‐induced proliferation and protection from the apoptotic effects of LY294002

Abstract: These results suggest a model whereby androgens promote an increase in the activity of the epidermal growth factor (EGF)-network by increasing ErbB1 levels, and this activity of is essential for androgen-induced proliferation and survival of the prostate cancer LNCaP cell line.

Cited by 42 publications

References 27 publications

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

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

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

Epidermal growth factor receptor activation in prostate cancer by three novel missense mutations

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