Characterization of the role of IL-6 in the progression of prostate cancer

Chung, Theodore D.; Yu, Jianqing; Spiotto, Michael T.; Bartkowski, Michelle; Simons, Jonathan W.

doi:10.1002/(sici)1097-0045(19990215)38:3<199::aid-pros4>3.0.co;2-h

Cited by 194 publications

(98 citation statements)

References 31 publications

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“…[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. We then analyzed how SHP-1 expression affects the IL-6 response in these cell lines.…”

Section: Discussionsupporting

confidence: 77%

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: Discussionsupporting

confidence: 77%

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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“…Our results suggest that the mechanism of IL-6 and HB-EGF-mediated NE differentiation (Chung et al, 1999;Kim et al, 2002) differs from the AM-induced mechanism as AM does not induce the phosphorylation of STAT3 at either Ser 727 or Tyr 705, the latest site shown to be critical to the differentiation event (Spiotto and Chung, 2000), nor the activation of the Erk-mitogen-activated protein kinase (MAPK) pathway. As in the case of HB-EGF, AM also did not induce cell cycle arrest as it was seen with IL-6.…”

Section: Discussionmentioning

confidence: 65%

Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates ‘neuroendocrine phenotype’ in LNCaP prostate tumor cells

et al. 2007

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Neuroendocrine (NE) differentiation in prostate cancer (CaP) has been reported to be an early marker associated with the development of androgen independence. The mechanisms by which CaP acquires NE properties are poorly understood. In this study, a putative role of adrenomedullin (AM) in the NE differentiation was investigated. The expression of AM and AM receptors (calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein-2 and -3 (RAMP2 and RAMP3) was evaluated after experimental manipulation of androgen status. Levels of AM mRNA and immunoreactive AM (ir-AM) increased four-to sevenfold in androgen-sensitive LNCaP cells after androgen withdrawal in vitro and in LNCaP xenografts in animals after castration. Treatment of LNCaP cells with androgen analogue (dihydrotestosterone; 10 À9 M) prevented the increase in AM mRNA and ir-AM levels. Interestingly, the expression of CRLR, RAMP2 and RAMP3 is not regulated by androgen status. We demonstrate that in the presence of serum, AM is able to induce an NE phenotype in LNCaP cells via CRLR/ RAMP2 and RAMP3, which includes extension of neuritic processes and expression of the neuron-specific enolase (NSE), producing cGMP in a dose-dependent manner, which is mediated by a pertussis toxin-sensitive GTP-binding protein. 8-bromo-cGMP mimicked the effects of AM on cell differentiation. We demonstrate that AM induces a G-kinase Ia translocation to the nucleus. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both AM and 8-bromocGMP. In noncastrated animals, administration of AM enhanced expression of NSE and chromogranin A in LNCaP xenografts with a significant increase of NSE levels in serum and no changes in tumor growth. In castrated animals, intraperitoneal injection of AM resulted in a 240718% (Po0.001) increase in tumor volume 36 days after treatment, indicating that the nature of effect of AM in CaP depends on the presence or absence of endogenous androgen. Together, these results demonstrate that AM may function as a mediator of NElike differentiation in culture as well as in vivo and indicate that its production may be important for tumor resurgence following androgen ablation.

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“…Then, to verify whether the survival role of IL-6 and Mcl-1 was specific for our in vitro model or was rather common in other IL-6-positive prostate cancer cell lines, we repeated the previous experiments with CNTO 328 and siRNAs by using the Du145 cell line. Du145 cells derive from a brain metastasis of prostate cancer and release in the medium amounts of IL-6 similar to those from LNCaP-IL-6 þ (Chung et al, 1999). By measuring the levels of cleaved CK18, we found that the treatment with CNTO 328 was able to significantly increase apoptosis in Du145 cells ( Figure 7a) and that transfection of Mcl-1 siRNA induced an increase of cleaved CK18 similar to that observed in LNCaP-IL-6 þ cells ( Figure 7b).…”

Section: Resultsmentioning

confidence: 99%

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

et al. 2006

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Characterization of the role of IL-6 in the progression of prostate cancer

Cited by 194 publications

References 31 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

Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates ‘neuroendocrine phenotype’ in LNCaP prostate tumor cells

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

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