Interleukin-6 Induces G1Arrest through Induction of p27Kip1, a Cyclin-Dependent Kinase Inhibitor, and Neuron-like Morphology in LNCaP Prostate Tumor Cells

Mori, Shunsuke; Murakami-Mori, Kaoru; Bonavida, Benjamin

doi:10.1006/bbrc.1999.0515

Cited by 90 publications

(69 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, as with leptin, IL-6 (40,41,53) or IGF-I (54) alone augments prostate cancer cell growth in androgen-independent DU145 and PC-3 cells but not in androgen-dependent LNCaP-FGC cells (Fig. 7, A and B).…”

Section: Discussionmentioning

confidence: 87%

Prostate Cancer Cell-Adipocyte Interaction

Onuma¹,

Bub

Rummel

et al. 2003

Journal of Biological Chemistry

164

View full text Add to dashboard Cite

Prostate cancer is one of the leading causes of death among men in the United States, and acquisition of hormone resistance (androgen independence) by cancer cells is a fatal event during the natural history of prostate cancer. Obesity is another serious health problem and has been shown to be associated with prostate cancer. However, little is known about the molecular basis of this association. Here we show that factor(s) secreted from adipocytes stimulate prostate cancer cell proliferation. Leptin is one of the major adipose cytokines, and it controls body weight homeostasis through food intake and energy expenditure. We identify leptin as a novel growth factor in androgen-independent prostate cancer cell growth. Strikingly, leptin stimulates cell proliferation specifically in androgen-independent DU145 and PC-3 prostate cancer cells but not in androgen-dependent LNCaP-FGC cells, although both cell types express functional leptin receptor isoforms. c-Jun NH 2 -terminal kinase (JNK) has been shown recently to play a crucial role in obesity and insulin resistance. Intriguingly, leptin induces JNK activation in androgen-independent prostate cancer cells, and the pharmacological inhibition of JNK blocked the leptin stimulation of androgenindependent prostate cancer cell proliferation. This suggests that JNK activation is required for leptin-mediated, androgen-independent prostate cancer cell proliferation. Furthermore, other cytokines produced by adipocytes and critical for body weight homeostasis cooperate with leptin in androgen-independent prostate cancer cell proliferation: interleukin-6 and insulin-like growth factor I demonstrate additive and synergistic effects on the leptin stimulation of androgen-independent prostate cancer cell proliferation, respectively. Therefore, adipose cytokines, as well as JNK, are key mediators between obesity and hormone-resistant prostate cancer and could be therapeutic targets.Prostate cancer is one of the leading causes of death among men in the United States. The disease is characterized by a prolonged natural history. Despite its relatively slow growth, a number of patients have persistent and/or recurrent disease. Initial treatment for many patients with recurrent disease is hormonal therapy to remove or decrease serum androgen as a potential growth stimulant for the prostate cancer. Although this approach is initially effective in the majority of patients, ultimately the disease becomes resistant to the loss of hormones, returns, and in many cases, culminates in the death of the patient. Thus, it is desired to develop effective therapies and preventives for hormone-resistant (androgen-independent) prostate cancer.Several lines of evidence indicate that obesity is a risk factor for prostate cancer. In particular, obesity is associated with clinical features characteristic of accelerated progression of prostate cancer: high mortality (1), prostatectomy at a younger age with high grade and more pathologically advanced cancer (2), and tendency for progression of stage B1-D1 ...

show abstract

Section: Discussionmentioning

confidence: 87%

Prostate Cancer Cell-Adipocyte Interaction

Onuma¹,

Bub

Rummel

et al. 2003

Journal of Biological Chemistry

164

View full text Add to dashboard Cite

show abstract

“…22 High levels of IL-6 are observed in the plasma of patients with prostate cancer, which correlate with more advanced stages of the disease, therapy resistance 23 and poor prognosis. 24 In in vitro experiments, IL-6 has been reported to affect cell proliferation and to induce neuroendocrine (NE) differentiation [25][26][27][28] of prostate cancer cells in a complicated manner depending on autocrine or paracrine cytokine action. [27][28][29] IL-6 binds to its receptor and mainly transduces signals through MAP kinase/ ERK, PI3K/AKT and STAT3 pathways.…”

mentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…Activation of membrane receptors coupled to adenylyl cyclase which leads to an increase in cytosolic cyclic AMP, as well as interleukins 1 and 6 induce the expression of neuroendocrine markers like NSE, secretory granules, and neurite extension (5)(6)(7)(8)(9). The stimulation of neuroendocrine differentiation by interleukin 6 has been shown to involve the induction of cyclin-dependent kinase inhibitor p27 Kip1 (7), as well as the tyrosine phosphorylation of epithelial and endothelial tyrosine kinase Etk/ Bmx through the activation of phosphatidylinositol 3Ј-kinase (6). Steroid removal from the culture medium was also shown to induce neuroendocrine differentiation (10,11).…”

mentioning

confidence: 99%