The Change in the Dihydrotestosterone Level in the Prostate Before and After Androgen Deprivation Therapy in Connection With Prostate Cancer Aggressiveness Using the Gleason Score

Nishiyama, Tsutomu; Ikarashi, Taro; Hashimoto, Yutaka; Wako, Koichi; Takahashi, Kota

doi:10.1016/j.juro.2007.05.138

Cited by 52 publications

(39 citation statements)

References 17 publications

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“…We could confirm these findings in our experimental models and found higher SRD5A1 levels in metastasized and hormone-refractory tumors. The association between SRD5A1 expression and Gleason score is in line with the observation that patients with a Gleason score of 7 to 10 PC had a smaller decline of intraprostatic DHT concentrations during hormonal therapy compared with patients with a Gleason score of 6 or lower (32). However, it must be noted that in CRPC samples, the Gleason score is less reliable and could give an erroneously high value.…”

Section: Discussionsupporting

confidence: 81%

Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

et al. 2010

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Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC. Cancer Res; 70(3); 1256–64

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Section: Discussionsupporting

confidence: 81%

Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

et al. 2010

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“…Notably, saturating concentrations of DHT (25 nM) were used in these studies to maximize the significance of the inhibitor effects; however, lower concentrations (1-10 nM) promoted a similar magnitude response (not shown). DHT levels in the prostate have not been accurately determined but are reported to be at least 10 -20 nM (19,20). Pretreatment with the AR antagonist flutamide (Fig.…”

Section: Dht-induced Erk Signaling Occurs Via Matrix Metalloproteinasmentioning

confidence: 99%

Paxillin Regulates Androgen- and Epidermal Growth Factor-induced MAPK Signaling and Cell Proliferation in Prostate Cancer Cells

Sen

O’Malley

Wang

et al. 2010

Journal of Biological Chemistry

102

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2 Genomic actions involve binding of androgens to ARs, which then translocate to the nucleus, bind to androgen-response elements, and alter gene expression. In contrast, ARs also induce rapid nongenomic signals that are generally mediated by cross-talk between the AR and either G-proteins or growth factor receptors (1-4). Although transcriptional effects of androgens have been extensively studied, mechanisms regulating nongenomic actions of androgens are poorly understood.One potential regulator of nongenomic androgen actions is paxillin. Paxillin is a multidomain adaptor protein that integrates many signals from integrins, cell surface receptors, and growth factors (10, 11). Through these interactions, paxillin regulates a variety of physiological functions, including matrix organization, cell motility, tissue remodeling, metastasis, gene expression, cell survival, and proliferation (10, 11). Paxillin is comprised of multiple structural domains that modulate protein-protein interactions (10) and numerous serine/threonine and tyrosine phosphorylation targets that act as docking sites for various signaling proteins. Phosphorylation of these sites by growth factor receptor-tyrosine kinases, Src kinases, and serine/threonine kinases regulate adaptor molecule binding that ultimately coordinates complex cell signaling pathways (10). The importance of paxillin in normal physiological functions is further evident from global paxillin knock-out studies, demonstrating that ablation of paxillin in mice is embryonic lethal (12,13).We previously demonstrated that in Xenopus oocytes, paxillin is essential for non-genomic androgen-induced Erk signaling and subsequent Erk-mediated oocyte maturation (5). Specifically, paxillin is required for synthesis and activation of MOS (the germ cell Raf homolog), which then promotes MEK and subsequently Erk signaling (5). Interestingly, Erk-mediated phosphorylation of paxillin is also required for androgen-induced oocyte maturation. Thus, in oocytes, paxillin is both an affector and effector of Erk signaling.Here we significantly extend our findings in Xenopus oocytes to a mammalian somatic system. Given the well defined function of androgens and Erk signaling (3, 6 -8) in prostate cancer

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“…The enzymatic conversion of DHEA to DHT has been shown to be essential for the activation of AR in LNCaP prostate cancer cells (Evaul et al 2010), while in vitro studies have shown that prostate cancer stromal cells and human LNCaP prostatic cancer cells coordinate activation of AR via synthesis of testosterone and DHT from DHEA (Mizokami et al 2009). In addition, increased expression of genes that code for the enzymes that convert DHEA into testosterone has been observed in CRPC (Stanbrough et al 2006), while cancerous prostatic tissue can synthesize more DHT than does benign prostatic tissue (Nishiyama et al 2007).…”

Section: Mechanisms Of Resistance To Castrationmentioning

confidence: 99%

GnRH agonists and the rapidly increasing use of combined androgen blockade in prostate cancer

Labrie¹

2014

Endocrine-Related Cancer

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The discovery of medical castration with GnRH agonists in 1979 rapidly replaced surgical castration and high doses of estrogens for the treatment of prostate cancer. Soon afterwards, it was discovered that androgens were made locally in the prostate from the inactive precursor DHEA of adrenal origin, a mechanism called intracrinology. Taking into account these novel facts, combined androgen blockade (CAB) using a pure antiandrogen combined with castration in order to block the two sources of androgens was first published in 1982. CAB was the first treatment shown in randomized and placebo-controlled trials to prolong life in prostate cancer, even at the metastatic stage. Most importantly, the results recently obtained with the novel pure antiandrogen enzalutamide as well as with abiraterone, an inhibitor of 17a-hydroxylase in castration-resistant prostate cancer, has revitalized the CAB concept. The effects of CAB observed on survival of heavily pretreated patients further demonstrates the importance of the androgens made locally in the prostate and are a strong motivation to apply CAB to efficiently block all sources of androgens earlier at start of treatment and, even better, before metastasis occurs. The future of research in this field thus seems to be centered on the development of more potent blockers of androgens formation and action in order to obtain better results at the metastatic stage and, for the localized stage, reduce the duration of treatment required to achieve complete apoptosis and control of prostate cancer proliferation before it reaches the metastatic or noncurable stage.

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The Change in the Dihydrotestosterone Level in the Prostate Before and After Androgen Deprivation Therapy in Connection With Prostate Cancer Aggressiveness Using the Gleason Score

Cited by 52 publications

References 17 publications

Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

Paxillin Regulates Androgen- and Epidermal Growth Factor-induced MAPK Signaling and Cell Proliferation in Prostate Cancer Cells

GnRH agonists and the rapidly increasing use of combined androgen blockade in prostate cancer

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