From HER2/Neu signal cascade to androgen receptor and its coactivators: A novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells

Yeh, Shuyuan; Lin, Hui Kuan; Kang, Hong-Yo; Thin, Tin Htwe; Lin, Ming Fong; Chang, Chawnshang

doi:10.1073/pnas.96.10.5458

Cited by 513 publications

(377 citation statements)

References 31 publications

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“…23 Increased PSA levels following treatment with other signal transduction modifiers has also been observed in other preclinical models. For example, while HER2/neu has been demonstrated to induce AR transactivation, stabilize AR protein levels and optimize binding of AR to promoter/enhancer regions, 24,25 the HER2/neu inhibitor Herceptin, was shown to markedly increase PSA levels/gram of tumor in LNCaP and CWR22R prostate cancer xenografts. 26 In addition, Korkmaz et al demonstrated that the histone deacetylase inhibitors trichostatin A, depsipeptide and sodium butyrate can enhance AR transcriptional activity in LNCaP cells leading to increased production of PSA.…”

Section: Discussionmentioning

confidence: 99%

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Collins

Carducci

Eisenberger

et al. 2007

Cancer Biology & Therapy

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Purpose-CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701.Methods-Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety.Results-CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 ± 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. Seven/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. Five/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo.Conclusions-Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.

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Section: Discussionmentioning

confidence: 99%

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Collins

Carducci

Eisenberger

et al. 2007

Cancer Biology & Therapy

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show abstract

“…45 This has been shown to occur in vivo in a cell-line model where HER2/neu regulates the phosphorylation of AR through a MAP kinase pathway. 46,47 IL-6 can also activate AR in the absence of androgen. 48 has been shown to act through Ser/Thr kinase Pim-1 and tryrosine kinase Ekt.…”

Section: Amplification Of the Armentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

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The clinical dilemma today in the management of prostate cancer (PCA) is to distinguish men who need definitive treatment from men who have indolent disease. As demonstrated most recently by the randomized Scandinavian trial evaluating the benefit of prostatectomy over Watchful Waiting, surgery significantly decreased the risk of death from PCA. However, this same study also suggests that 19 men need to be treated to benefit one man. Given the high prevalence of the disease, the aging of the population, and the potential morbidity of treatment, the ability to distinguish aggressive from indolent forms of PCA is critical. Treatment for advanced PCA begins with androgen ablation, but eventually hormone-refractory (HR) PCA emerges. Novel therapies are in various stages of clinical trials, including kinase inhibitors, antisense oligonucleotides, and inhibitors of heat-shock proteins. The discovery of novel therapeutic approaches is an active area of clinical research. Eliminating HR PCA before it advances is a high priority in the biomarker field. Therefore, the development of molecular signatures of lethal PCA are critical. In addition, the recent discovery that a significant percentage of PCAs harbor a TMPRSS2-ETS gene fusion suggests that targeting either the ETS transcription factors or the fusion product may offer a novel approach to therapy. However, in 2007, the mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s.

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“…HER2/neu belongs to the EGFR family of receptor tyrosine kinases and has been implicated in androgen-independent prostate cancer growth by activation of the androgen receptor pathway. 70,71 The HER2/neu pathway also promotes cell survival through the PI-3/Akt pathway 72 by inactivating the pro-apoptotic protein Bad. 73 Interestingly, the PI-3/ Akt pathway activates the NF-kB transcription factor which mediates several cellular processes including cell growth, inflammatory responses and apoptosis 63 and inhibition of TGF-b signaling by increasing Smad7 expression.…”

Section: (3) Antagonistic Signaling Pathways Of Tgf-b Mediated Apoptomentioning

confidence: 99%

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

Anglin

Glassman

Kyprianou

2002

Prostate Cancer Prostatic Dis

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a 1 -Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based a 1 -antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an a 1 -adrenoceptor independent mechanism potentially involving activation of the TGF-b signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived a 1 -adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases.

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From HER2/Neu signal cascade to androgen receptor and its coactivators: A novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells

Cited by 513 publications

References 31 publications

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Induction of prostate apoptosis by α1-adrenoceptor antagonists: mechanistic significance of the quinazoline component

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