Zsofia Kiss and Paramita M Ghosh
The androgen receptor (AR) plays a key role in the development and progression of prostate cancer (CaP). Since the mid-1990s, reports in the literature pointed out higher incidences of CaP in some select groups, such as airline pilots and night shift workers in comparison with those working regular hours. The common finding in these ‘high-risk’ groups was that they all experienced a deregulation of the body’s internal circadian rhythm. Here, we discuss how the circadian rhythm affects androgen levels and modulates CaP development and progression. Circadian rhythmicity of androgen production is lost in CaP patients, with the clock genes Per1 and Per2 decreasing, and Bmal1 increasing, in these individuals. Periodic expression of the clock genes was restored upon administration of the neurohormone melatonin, thereby suppressing CaP progression. Activation of the melatonin receptors and the AR antagonized each other, and therefore the tumour-suppressive effects of melatonin and the clock genes were most clearly observed in the absence of androgens, that is, in conjunction with androgen deprivation therapy (ADT). In addition, a large-scale study found that high-dose radiation was more effective in CaP patients when it was delivered before 17:00 h, compared with those delivered after 17:00 h, suggesting that the therapy was more effective when delivered in synchrony with the patient’s circadian clock. As CaP patients are shown to become easily resistant to new therapies, perhaps circadian delivery of these therapeutic agents or delivery in conjunction with melatonin and its novel analogs should be tested to see if they prevent this resistance.
Rosalinda M Savoy and Paramita M Ghosh
A new paper by Tawadros et al. in Endocrine-Related Cancer demonstrates a link between macrophage migration inhibitory factor and neuroendocrine differentiation in prostate cancer. This paper may have implications in explaining the effect of prostatitis and chronic inflammation on the development of aggressive prostate cancer.
Rosalinda M Savoy and Paramita M Ghosh
Estrogens were once used for the treatment of prostate cancer (PC). They may still be used in various parts of the world to that effect. Recent developments in the understanding of a role for estrogen receptor β (ERβ) in the development and progression of this disease resurrect the discussion on the intertwined roles of ERβ and the androgen receptor (AR) in promoting PC. A new article by Zellweger et al. in Endocrine-Related Cancer investigates the expression and assesses the activity of ERα and ERβ as well as the AR, in addition to a phosphorylated form of AR in hormone-naïve and castration-resistant PC.
Rosalinda M Savoy and Paramita M Ghosh
Filamin A (FlnA) has been associated with actin as cytoskeleton regulator. Recently its role in the cell has come under scrutiny for FlnA's involvement in cancer development. FlnA was originally revealed as a cancer-promoting protein, involved in invasion and metastasis. However, recent studies have also found that under certain conditions, it prevented tumor formation or progression, confusing the precise function of FlnA in cancer development. Here, we try to decipher the role of FlnA in cancer and the implications for its dual role. We propose that differences in subcellular localization of FlnA dictate its role in cancer development. In the cytoplasm, FlnA functions in various growth signaling pathways, such as vascular endothelial growth factor, in addition to being involved in cell migration and adhesion pathways, such as R-Ras and integrin signaling. Involvement in these pathways and various others has shown a correlation between high cytoplasmic FlnA levels and invasive cancers. However, an active cleaved form of FlnA can localize to the nucleus rather than the cytoplasm and its interaction with transcription factors has been linked to a decrease in invasiveness of cancers. Therefore, overexpression of FlnA has a tumor-promoting effect, only when it is localized to the cytoplasm, whereas if FlnA undergoes proteolysis and the resulting C-terminal fragment localizes to the nucleus, it acts to suppress tumor growth and inhibit metastasis. Development of drugs to target FlnA and cause cleavage and subsequent localization to the nucleus could be a new and potent field of research in treating cancer.
Paramita M Ghosh and Allen C Gao
Androgen deprivation therapy (ADT) is known to cause bone loss in a majority of patients with castration-resistant prostate cancer (CRPC). A study published in this issue of Endocrine-Related Cancer by Ottewell and colleagues shows that ADT increased bone resorption and triggered growth of disseminated prostate cancer (CaP) cells to form bone metastasis using an in vivo model. However, prevention of bone decay by weekly administration of zoledronic acid (ZOL) at the time of castration prevented ADT-induced tumor growth in bone. Recently, two publications from Japan have demonstrated that ZOL combined with ADT improved outcomes for patients with treatment-naïve CaP with bone metastasis. The mechanistic cause for these patients having an improved overall survival compared with those who were treated with ZOL after ADT initiation or before metastasis development was never explained. Ottewell and colleague's study now suggests that it is the bone loss caused by ADT that promoted bone metastasis, and if ZOL is administered at the time of ADT initiation, it would prevent this bone loss and prolong skeletal-related event-free survival.
Amina Zoubeidi and Paramita M Ghosh
In this issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of hormone ablation as treatment for metastatic prostate cancer. Our understanding has evolved from the observation that androgen withdrawal, either surgical or pharmacological, resulted in prostatic atrophy in animal models, to its application in patients, to investigation of the mysterious way in which prostate cancer escapes androgen dependence. We are now in an era of novel AR pathway inhibitors, the combination of androgen ablation with chemotherapy, PARP inhibitors, immunotherapies, guided radiotherapy, and novel drug application based upon genetic testing of individual tumors. In this special issue, we bring together a collection of eight reviews that cover not only the history of 80 years of progress after the initial identification of androgen ablation as an effective treatment of prostate cancer, but subsequent improvements in the understanding of the biology of the disease, development of novel treatment paradigms, resistance to those treatments and disease progression following that resistance.
Paramita M Ghosh, Shazli N Malik, Roble G Bedolla, Yu Wang, Margarita Mikhailova, Thomas J Prihoda, Dean A Troyer, and Jeffrey I Kreisberg
In a previous report, we showed that increased activation of Akt, a downstream effector of phosphoinositide 3-kinase (PI3K) together with decreased activation of extracellular-signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) family, predicted poor clinical outcome in prostate cancer (
Cancer Research 64 5232–5236
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Honglin Chen, Stephen J Libertini, Michael George, Satya Dandekar, Clifford G Tepper, Bushra Al-Bataina, Hsing-Jien Kung, Paramita M Ghosh, and Maria Mudryj
Prostate carcinoma (CaP) is a heterogeneous multifocal disease where gene expression and regulation are altered not only with disease progression but also between metastatic lesions. The androgen receptor (AR) regulates the growth of metastatic CaPs; however, sensitivity to androgen ablation is short lived, yielding to emergence of castrate-resistant CaP (CRCaP). CRCaP prostate cancers continue to express the AR, a pivotal prostate regulator, but it is not known whether the AR targets similar or different genes in different castrate-resistant cells. In this study, we investigated AR binding and AR-dependent transcription in two related castrate-resistant cell lines derived from androgen-dependent CWR22-relapsed tumors: CWR22Rv1 (Rv1) and CWR-R1 (R1). Expression microarray analysis revealed that R1 and Rv1 cells had significantly different gene expression profiles individually and in response to androgen. In contrast, AR chromatin immunoprecipitation (ChIP) combined with promoter DNA microarrays (ChIP-on-chip) studies showed that they have a similar AR-binding profile. Coupling of the microarray study with ChIP-on-chip analysis identified direct AR targets. The most prominent function of transcripts that were direct AR targets was transcriptional regulation, although only one transcriptional regulator, CCAAT/enhancer binding protein δ, was commonly regulated in both lines. Our results indicate that the AR regulates the expression of different transcripts in the two lines, and demonstrate the versatility of the AR-regulated gene expression program in prostate tumors.
Benjamin A Mooso, Ruth L Vinall, Clifford G Tepper, Rosalinda M Savoy, Jean P Cheung, Sheetal Singh, Salma Siddiqui, Yu Wang, Roble G Bedolla, Anthony Martinez, Maria Mudryj, Hsing-Jien Kung, Ralph W deVere White, and Paramita M Ghosh
As prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280 kDa structural protein Filamin A (FlnA) to a 90 kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein combined polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence, both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration, indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP.