Mechanisms of Androgen-Refractory Prostate Cancer

Debes, José D.; Tindall, Donald J.

doi:10.1056/nejmp048178

Cited by 491 publications

(394 citation statements)

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“…Androgen receptor (AR) signalling is crucial for prostate tumour growth [9][10][11][12][13] . When bound to androgens, ARs translocate to the nucleus and transactivate target genes by interacting with other transcription factors such as forkhead-box A1 (FOXA1) 10 .…”

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confidence: 99%

“…When bound to androgens, ARs translocate to the nucleus and transactivate target genes by interacting with other transcription factors such as forkhead-box A1 (FOXA1) 10 . Although the molecular mechanisms underlying prostate cancer progression to lethal hormone refractory prostate cancer (HRPC) [9][10][11][12][13] are incompletely understood, activation of downstream signals by hypersensitive or overexpressed ARs is considered to be important. The epigenetic status of prostate cancer cells is modulated by AR binding and the subsequent recruitment of co-activators or co-repressors [14][15][16][17][18] .…”

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confidence: 99%

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TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.

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TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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“…Multiple mechanisms have been identified that contribute to the androgen sensitive (AS) transition to the AI phenotype [1][2][3][4][5]. In the outlaw pathway, receptor tyrosine kinases are activated, and the androgen receptor (AR) is phosphorylated by either the AKT (protein kinase B) or the mitogen-activated protein kinase (MAPK) pathway, producing a ligand-independent AR.…”

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confidence: 99%

Development of the VCaP androgen-independent model of prostate cancer

Loberg

John

Day

et al. 2006

Urologic Oncology: Seminars and Original Investigations

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Prostate epithelial cell growth is dependent on the presence of androgens and the transition of prostate cancer to an androgen independent phenotype results in a highly aggressive, currently incurable cancer. We have developed a new preclinical model of androgen independent prostate cancer derived from the VCaP prostate cancer epithelial cell line. VCaP cells were subcutaneously implanted and serially passaged in castrated male SCID mice. Androgen independence was confirmed by WST-1 (a tetrazolium salt) cell proliferation assay in the absence or presence of dihydrotesterone (DHT) (1 -100 nM). VCaP androgen sensitive (VAS) cells responded dose dependently to DHT whereas VCaP androgen independent (VAI) cells did not alter their proliferation in response to DHT. Gene expression of androgen receptor, Bcl-2, DD3, prostate acid phosphatase, STEAP, and survivin was determined by PCR amplification. Bcl-2 expression was upregulated in the VAI lines compared to the VAS suggesting a possible mechanism of androgen independence. Futhermore, tumorassociated -angiogenesis was assessed by immunofluorescence confocal microscopy of CD31. VAI tumors demonstrated enhanced angiogenesis compared to VAS tumors. These results demonstrate the development of a novel model of prostate cancer androgen independence and provide a new system to study angiogenesis and the transition to androgen independence.

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“…Mutations in the AR can increase its affinity for ligand binding, permitting activation by nonandrogenic hormones or even antagonists (Nelson et al, 2003;Debes and Tindall, 2004). Overexpression of AR increases the sensitivity of prostate cancer cells to low levels of androgens, which promotes androgen-independent growth (Linja et al, 2001;Chen et al, 2004;Debes and Tindall, 2004).…”

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confidence: 99%

“…Overexpression of AR increases the sensitivity of prostate cancer cells to low levels of androgens, which promotes androgen-independent growth (Linja et al, 2001;Chen et al, 2004;Debes and Tindall, 2004). Studies also showed that AR, as a crucial factor, determines the molecular alterations required for the development of refractory prostate cancer (Debes and Tindall, 2004). In general, the AR is bound to heat shock proteins, in the cytoplasm.…”

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Phellinus linteus activates different pathways to induce apoptosis in prostate cancer cells

et al. 2007

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It is known that polysaccharides extracted from the Phellinus linteus (PL) mushroom possess antitumour activity. We previously have demonstrated that high doses of PL render murine or human lung cancer cells susceptible to apoptosis. However, the molecular mechanisms of PL-mediated apoptosis have not been fully explored. In this study, we demonstrate that LNCaP cells expressing the androgen receptor (AR) are highly susceptible to apoptosis in response to treatment with high doses of PL. In this process, caspase 8 and its downstream effectors (such as BID), as well as ER stress-related, apoptotic signalling, are activated. In contrast, a moderate amount of apoptosis occurs in PC3 cells (that lack AR) after the same treatment, which does not activate ER-mediated apoptotic signalling. We also show that, in the process of PL-induced apoptosis, caspase 2 is induced in LNCaP cells, but not in PC3 cells. However, LNCaP cells that express a mutated AR or LNCaP cells treated with a caspase 2 inhibitor blocked ER stress-induced apoptotic signals. The magnitudes of the induction of apoptosis in these cells are comparable with what occurred in the PC3 cells. The data demonstrate that high doses of PL activate the AR-dependent and independent apoptotic pathways. Our study also suggests that caspase 2 is a key target in the determination of the susceptibility of prostate cancer cells to PL-induced apoptosis. Phellinus linteus (PL) is among a number of well-known medicinal mushrooms from Asian countries, which have been taken orally since ancient times as a health-promoting dietary supplement and an adjuvant to combat viral and bacterial infections. PL, after purification, shows a relatively homogeneous molecular weight distribution on gel permeation HPLC and is estimated to be around 150 kDa from the retention time on HPLC pullulan molecular markers (Song et al, 1995). The main components of PL are polysaccharides (Song et al, 1995;Lorenzen and Anke, 1998;Borchers et al, 1999;Han et al, 1999). Many studies demonstrated that polysaccharides from various substances, including PL, are remarkably effective in inhibiting the growth of tumours without toxic side effects. Studies also showed that polysaccharides in PL are able to suppress tumours, either indirectly by enhancing the host's immune system or directly by inducing apoptosis in tumour cells (Chihara et al, 1969;Chung et al, 1982;Cun et al, 1994;Wasser, 2002;Collins et al, 2006;Guo et al, 2006). Therefore, the antitumour, antiangiogenic and immunomodulatory effects of PL are potential areas for developing novel pharmaceutical products. However, the underlying molecular mechanisms of the antitumour effects of PL have not yet been fully explored.Changes in the androgen receptor (AR) have been indicated to contribute to the development of prostate cancer and are a serious challenge to effective treatment. Mutations in the AR can increase its affinity for ligand binding, permitting activation by nonandrogenic hormones or even antagonists (Nelson et al, 2003;Debes and Tindall, ...

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Mechanisms of Androgen-Refractory Prostate Cancer

Cited by 491 publications

References 5 publications

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

Development of the VCaP androgen-independent model of prostate cancer

Phellinus linteus activates different pathways to induce apoptosis in prostate cancer cells

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