Mitogen‐activated protein kinase pathway is involved in androgen‐independent <i>PSA</i> gene expression in LNCaP cells

Franco, Omar E.; Onishi, Takehisa; Yamakawa, Kensuke; Arima, Kiminobu; Yanagawa, Makoto; Sugimura, Yoshiki; Kawamura, J

doi:10.1002/pros.10258

Cited by 26 publications

(18 citation statements)

References 21 publications

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“…The role of the KGF/p38 pathway in inducing expression and stimulation of the AR during differentiation of the TAP may have considerable significance in androgen independent disease. It has previously been suggested that growth factors, including KGF, IGF and EGF, can activate the AR via MAPK pathways (Culig et al, 1996;Culig et al, 1994;Franco et al, 2003;Planz et al, 2001) and this pathway has previously implicated in hormone-resistant prostate cancer (Lin et al, 2001;Uzgare and Isaacs, 2004;Uzgare et al, 2003). Interestingly, we observed that KGF/p38 induced PSA production, consistent with the phenomenon of crosstalk between the KGF and AR pathways.…”

Section: Discussionsupporting

confidence: 88%

KGF suppresses α2β1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium

Heer

Collins

Robson

et al. 2006

Journal of Cell Science

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Prostate epithelial stem cells are self-renewing cells capable of differentiation into prostate epithelium, and are thought to contribute towards both benign and malignant conditions in the human prostate. We have previously demonstrated that prostate epithelial basal cells express high levels of integrin α2β1 and this population can be subdivided into stem (α2β1hi CD133+) and transient-amplifying population (TAP) cells (α2β1hi CD133-). However, the molecular mechanism(s) controlling the commitment and regulation of these cells towards differentiated epithelium remains unclear. Here, we demonstrate that β1 integrin function is required for the maintenance of basal prostatic epithelial cells and suppression of its function by either methylcellulose or, more specifically, β1-blocking antibody (80 μg/ml) induces differentiation, with associated expression of the differentiation-specific markers prostate acid phosphatase (PAP) and cytokeratin 18 (CK18). Keratinocyte growth factor (KGF), a stromal-derived growth factor, has previously been implicated in prostate organogenesis using in vitro tissue recombination experiments. We show that treatment with KGF (10 ng/ml) potently induces epithelial differentiation with concomitant suppression of α2β1 integrin expression as well as the induction of androgen receptor expression. Specifically, p38-MAPK appears to be involved and the presence of SB202190, a p38 inhibitor, significantly blocks KGF-induced differentiation. Furthermore, the expression of the high-affinity receptor tyrosine kinase to KGF (FGFR2) is predominantly detectable in α2β1hi CD133- TAP cells when compared with stem cells (α2β1hi CD133+), which would therefore be relatively unresponsive to the differentiating effect of KGF. Taken together, using a human primary culture model, we have demonstrated key roles for interactions between KGF and integrin-mediated function in the regulation of prostate epithelial differentiation.

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Section: Discussionsupporting

confidence: 88%

KGF suppresses α2β1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium

Heer

Collins

Robson

et al. 2006

Journal of Cell Science

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“…Previous studies revealed that AR function is influenced by Ras/MAP kinase interactions with AR-associated proteins (Culig et al 2005b). Elevation of PSA levels is also a p44/p42-sensitive phenomenon in androgen-independent conditions (Franco et al 2003). MDA PCa 2b cells after incubation with IL-6 showed an increase in phosphorylation of p44/p42 kinases.…”

Section: Discussionmentioning

confidence: 98%

Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

Malinowska¹,

Neuwirt²,

Cavarretta³

et al. 2009

Endocrine-Related Cancer

145

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It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptorpositive tumours in vitro and in vivo through activation of the androgen receptor.

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“…ERK activation under androgen-independent conditions may contribute to the increase in PSA, an AR target gene. (68) In a mouse model of prostate cancer, activation of both ERK and p38 correlated with cell proliferation and the initiation of prostate cancer while all three major MAPKs were inactivated in advanced stage disease. (69) Similar to other tissues, there is very good correlation between JNK activation and apoptosis in prostate cancer cells; in fact, JNK activation is required for apoptosis induced by various agents in prostate cancer cells in vitro.…”

Section: Mapk Signalingmentioning

confidence: 99%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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Mitogen‐activated protein kinase pathway is involved in androgen‐independent PSA gene expression in LNCaP cells

Abstract: Our data suggest that enhanced androgen-independent PSA gene expression in MAP kinase-induced LNCaP cells is mediated, at least in part, by the "B" motif of the PSA promoter.

Cited by 26 publications

References 21 publications

KGF suppresses α2β1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium

KGF suppresses α2β1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium

Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

Androgen signaling and its interactions with other signaling pathways in prostate cancer

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