A cross-talk between the androgen receptor and the epidermal growth factor receptor leads to p38MAPK-dependent activation of mTOR and cyclinD1 expression in prostate and lung cancer cells

Recchia, Anna Grazia; Musti, Anna Maria; Lanzino, Marilena; Panno, Maria Luisa; Turano, Ermanna; Zumpano, Rachele; Belfiore, Antonino; Andò, Sebastiano; Maggiolini, Marcello

doi:10.1016/j.biocel.2008.07.004

Cited by 64 publications

(53 citation statements)

References 61 publications

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“…Recent studies using recombinant ES also showed the strongest response in LLC and NSCLC (11)(12)(13). In this respect, it is noteworthy that elevated AR expression in the lung has been implicated in promoting the tumor development and progression (16,33,34). Thus, the potent tumor regression could also be attributed to AR antagonism in lung cancer, which may further provide an opportunity to revisit the unsolved molecular mechanism of insoluble ES.…”

Section: Discussionmentioning

confidence: 99%

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

Lee¹,

Isayeva²,

Larson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Acquired resistance to androgen receptor (AR)-targeted therapies compels the development of novel treatment strategies for castration-resistant prostate cancer (CRPC). Here, we report a profound effect of endostatin on prostate cancer cells by efficient intracellular trafficking, direct interaction with AR, reduction of nuclear AR level, and down-regulation of AR-target gene transcription. Structural modeling followed by functional analyses further revealed that phenylalanine-rich α1-helix in endostatin-which shares structural similarity with noncanonical nuclear receptor box in ARantagonizes AR transcriptional activity by occupying the activation function (AF)-2 binding interface for coactivators and N-terminal AR AF-1. Together, our data suggest that endostatin can be recognized as an endogenous AR inhibitor that impairs receptor function through protein-protein interaction. These findings provide new insights into endostatin whose antitumor effect is not limited to inhibiting angiogenesis, but can be translated to suppressing AR-mediated disease progression in CRPC.endostatin | androgen receptor | prostate cancer | chemoresistance

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Section: Discussionmentioning

confidence: 99%

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

Lee¹,

Isayeva²,

Larson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The ERK1/2 and p38 MAPK signaling pathways can be activated in response to a diverse range of extracellular stimuli including mitogens, growth factors, and cytokines (Baccarini 2005;Meloche and Pouysségur 2007;Roux and Blenis 2004) and are important targets in the diagnosis and treatment of cancer (Roberts and Der 2007). Suppression of the activated EGFR and ERK1/2 and p38 MAPKs as well as Akt signaling pathways led to inhibition of the proliferation of A549 cells (Baldys et al 2007;Nguyen et al 2004;Recchia et al 2009;Su et al 2010). There has been the cross-talk in EGFR and c-Met pathways in A549 cells which is related to the A549 cell proliferation (Puri and Salgia 2008).…”

Section: Bufalin Reduces the Receptor Phosphorylation And/or Protein mentioning

confidence: 99%

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

et al. 2010

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Bufalin, a naturally occurring small-molecule compound from Traditional Chinese Medicine (TCM) Chansu showed inhibitory effects against human prostate, hepatocellular, endometrial and ovarian cancer cells, and leukemia cells. However, whether or not bufalin has inhibitory activity against the proliferation of human non-small cell lung cancer (NSCLC) cells is unclear. The aim of this study is to study the effects of bufalin on the proliferation of NSCLC and its molecular mechanisms of action. The cancer cell proliferation was measured by MTT assay. The apoptosis and cell cycle distribution were analyzed by flow cytometry. The protein expressions and phosphorylation in the cancer cells were detected by Western blot analysis. In the present study, we have demonstrated that bufalin suppressed the proliferation of human NSCLC A549 cell line in time-and dosedependent manners. Bufalin induced the apoptosis and cell cycle arrest by affecting the protein expressions of Bcl-2/Bax, cytochrome c, caspase-3, PARP, p53, p21WAF1, cyclinD1, and COX-2 in A549 cells. In addition, bufalin reduced the protein levels of receptor expressions and/or phosphorylation of VEGFR1, VEGFR2, EGFR and/or c-Met in A549 cells. Furthermore, bufalin inhibited the protein expressions and phosphorylation of Akt, NF-jB, p44/42 MAPK (ERK1/2) and p38 MAPK in A549 cells. Our results suggest that bufalin inhibits the human lung cancer cell proliferation via VEGFR1/VEGFR2/EGFR/cMet-Akt/p44/42/p38-NF-jB signaling pathways; bufalin may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of human NSCLC.

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“…These signalling pathways may activate the AR without ligand, culminating in androgenreceptor signalling, leading to cellular proliferation, migration, and survival. The references for the reactions cited in Figure 1 are as follows: Reaction 1, Heinlein and Chang, 2004; Reaction 2, Heinlein and Chang, 2004;Reaction 3, Heinlein and Chang, 2004;Reaction 4, Heinlein and Chang, 2004;Reaction 5, Heinlein and Chang, 2004;Reaction 6, Heinlein and Chang, 2004;Reaction 7, Brass et al, 1995;Ravenna et al, 1995;Itoh et al, 1998;Schwartz et al, 1998;Heinlein and Chang, 2004;Hammarsten et al, 2007;Pignon et al, 2009;Reaction 8, Nishi et al, 1996;Reaction 9, Traish and Wotiz, 1987;St-Arnaud et al, 1988;Reaction 10, Sugita et al, 2004;Gregory et al, 2005;Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 11, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 12, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 13, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 14, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009. Abbreviations: AKT, protein kinase B; AR, androgen receptor; ARE, androgen response element; 5a-DHT, d...…”

Section: Loss Of Regulation Of Egfr Expression In Pca By Androgens Stmentioning

confidence: 99%

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

2009

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Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve 'cross-talk' between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa.

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A cross-talk between the androgen receptor and the epidermal growth factor receptor leads to p38MAPK-dependent activation of mTOR and cyclinD1 expression in prostate and lung cancer cells

Cited by 64 publications

References 61 publications

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

Endostatin: A novel inhibitor of androgen receptor function in prostate cancer

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

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