Interleukin‐6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression

Lee, Soo Ok; Chun, Jae Yeon; Nadiminty, Nagalakshmi; Lou, Wei; Gao, Allen C.

doi:10.1002/pros.20553

Cited by 82 publications

(93 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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. 30 It has been shown in oligodendrocytes from the motheaten mice, which have a genetic defect in the SHP-1 gene, that SHP-1 expression controls the activation of STAT3 by IL-6 signaling.…”

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

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

show abstract

“…This enhanced sensitivity of LNCaP/IL-6#1 to androgen withdrawal was more remarkable in vivo; that is, after castration, LNCaP/IL-6#1 tumour rapidly regressed and completely disappeared. According to previously reported studies, the effects of IL-6 on the growth of LNCaP cells seem to be puzzling with some groups showing growth stimulation, whereas others showing growth inhibition Lee et al, 2003Lee et al, , 2007Jia et al, 2004). For example, Lee et al (2007) reported the bifunctional action of IL-6 according to the manner of its secretion; that is, IL-6 acts as a growth inhibitor for LNCaP cells by a paracrine mechanism, whereas endogenously produced IL-6 stimulates LNCaP cell growth by an autocrine mechanism.…”

Section: Discussionmentioning

confidence: 98%

“…According to previously reported studies, the effects of IL-6 on the growth of LNCaP cells seem to be puzzling with some groups showing growth stimulation, whereas others showing growth inhibition Lee et al, 2003Lee et al, , 2007Jia et al, 2004). For example, Lee et al (2007) reported the bifunctional action of IL-6 according to the manner of its secretion; that is, IL-6 acts as a growth inhibitor for LNCaP cells by a paracrine mechanism, whereas endogenously produced IL-6 stimulates LNCaP cell growth by an autocrine mechanism. As most of the previously observed effects of IL-6 on the growth of prostate cancer cells were examined in vitro, this study is the first to demonstrate the following evidence that overexpression of IL-6 in LNCaP cells enhanced their sensitivity to androgen withdrawal both in vitro and in vivo, resulting in marked growth inhibition immediately after androgen ablation.…”

Section: Discussionmentioning

confidence: 98%

“…Consequently, it has been suggested that crosstalk between AR and IL-6 may have an important function in the activation of AR signalling in a ligand-independent manner (Okamoto et al, 1997;Hobisch et al, 1998;Lou et al, 2000;Lin et al, 2001;Ueda et al, 2002a, b;Lee et al, 2003). To date, however, it remains controversial whether IL-6 confers a malignant phenotype on prostate cancer cells, particularly under an androgen-deprived condition (Okamoto et al, 1997;Hobisch et al, 1998Hobisch et al, , 2001Mori et al, 1999;Lou et al, 2000;Deeble et al, 2001;Lin et al, 2001;Ueda et al, 2002a, b;Lee et al, 2003Lee et al, , 2007Jia et al, 2004). Accordingly, in this study, we established the IL-6-overexpressing LNCaP cells (i.e., LNCaP/IL-6#1), and assessed the effects of IL-6 secreted through an autocrine manner on their phenotype before and after androgen withdrawal.…”

Section: Discussionmentioning

confidence: 99%

“…In recent studies, it was also demonstrated that modulations of three major downstream signalling pathways, MAPK, Akt and STAT3, are involved in AI transactivation of AR by IL-6 (Yang et al, 2003). However, the reported actions of IL-6 in conferring malignant phenotype to prostate cancer cells remain controversial, with some studies showing positive findings (Okamoto et al, 1997;Hobisch et al, 1998;Lou et al, 2000;Lin et al, 2001;Ueda et al, 2002a, b;Lee et al, 2003), and others showing negative findings (Mori et al, 1999;Deeble et al, 2001;Hobisch et al, 2001;Jia et al, 2004;Lee et al, 2007). It also remains controversial which signal transduction pathway is most dominantly associated with the transactivation of AR induced by IL-6 (Chen et al, 2000;Chung et al, 2000;Corcoran and Costello, 2003;Yang et al, 2003).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Enhanced sensitivity to androgen withdrawal due to overexpression of interleukin-6 in androgen-dependent human prostate cancer LNCaP cells

et al. 2009

View full text Add to dashboard Cite

Background: The objective of this study was to investigate the effects of interleukin-6 (IL-6) overexpression in androgen-dependent prostate cancer LNCaP cells on their phenotype under an androgen-deprived condition. Methods: We established IL-6-overexpressing LNCaP (LNCaP/IL-6) by introducing the expression vector containing IL-6 cDNA. Changes in the phenotype in LNCaP/IL-6 were compared with that in LNCaP transfected with control vector alone (LNCaP/Co). Results: In vitro , the growth of LNCaP/IL-6 was significantly inferior to that of LNCaP/Co under an androgen-deprived condition. Similarly, LNCaP/IL-6 tumour in nude mice rapidly regressed after castration; however, LNCaP/Co tumour growth was transiently inhibited after castration and then continuously accelerated. After androgen withdrawal, expression levels of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and Akt in LNCaP/IL-6 were markedly upregulated compared with those in LNCaP/Co; however, additional treatment with specific inhibitor of the MAPK or Akt signalling pathway significantly inhibited the growth of LNCaP/IL-6 compared with that of LNCaP/Co. Furthermore, gene microarray analyses showed that androgen deprivation resulted in differential expression of genes involved in growth, apoptotsis and tumorigenesis between LNCaP/Co and LNCaP/IL-6. Conclusion: Excessive secretion of IL-6 by LNCaP cells in an autocrine manner may have a suppressive function in their growth and acquisition of androgen-independent phenotype under an androgen-deprived condition.

show abstract

The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer

Yuan

Cen

et al. 2022

Clinical & Translational Med

View full text Add to dashboard Cite

Background Lineage plasticity in prostate cancer (PCa) has emerged as an important mechanism leading to the onset of therapy‐ and castration‐resistant PCa (t‐CRPC), which is closely associated with cancer stem cell (CSC) activity. This study is to identify critical driver(s) with mechanism of action and explore new targeting strategy. Methods Various PCa cell lines with different genetic manipulations were subjected to in vitro prostasphere assay, cell viability assay and in vivo stemness potential. In addition, bioinformatic analyses such as Ingenuity pathway and Gene Set Enrichment Analysis were carried out to determine clinical relevance. The in vivo anti‐tumour activity of JAK or STAT1 inhibitors was examined in clinically relevant t‐CRPC model. Results We demonstrated the role of interferon‐related signalling pathway in promoting PCa stemness, which correlated with significant elevation of interferon related DNA damage resistance signature genes in metastatic PCa. Inhibition of JAK‐STAT1 signalling suppresses the in vitro and in vivo CSC capabilities. Mechanistically, IFIT5, a unique downstream effector of JAK‐STAT1 pathway, can facilitate the acquisition of stemness properties in PCa by accelerating the turnover of specific microRNAs (such as miR‐128 and ‐101) that can target several CSC genes (such as BMI1, NANOG, and SOX2). Consistently, knocking down IFIT5 in t‐CRPC cell can significantly reduce in vitro prostasphere formation as well as decrease in vivo tumour initiating capability. Conclusions This study provides a critical role of STAT1‐IFIT5 in the acquisition of PCSC and highlights clinical translation of JAK or STAT1 inhibitors to prevent the outgrowth of t‐CRPC.

show abstract

Interleukin‐6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression

Cited by 82 publications

References 33 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

Enhanced sensitivity to androgen withdrawal due to overexpression of interleukin-6 in androgen-dependent human prostate cancer LNCaP cells

The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer

Contact Info

Product

Resources

About