Transition from androgenic to neurosteroidal action of 5α-androstane-3α, 17β-diol through the type A γ-aminobutyric acid receptor in prostate cancer progression

Ding, Xia; Lai, Doan V.; Wu, Weijuan; Webb, Zachary D.; Yang, Qing; Zhao, Lichao; Yu, Zhongxin; Thorpe, Jessica E.; Disch, Bryan C.; Ihnat, Michael A.; Jayaraman, Muralidharan; Dhanasekaran, Danny N.; Stratton, Kelly; Cookson, Michael S.; Fung, Kar Ming; Lin, Hsueh Kung

doi:10.1016/j.jsbmb.2017.11.006

Cited by 13 publications

(14 citation statements)

References 65 publications

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“…In prostate cancer 282,283 GABA A -R is expressed in cancerous gland tissue, but absent normal tissue. Thus, this chlorine channel brings about the GABAergic system to aggravate the situation in prostate cancer.…”

Section: Classical Central Nervous System Neurotransmitters (Dopaminementioning

confidence: 99%

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Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Cervantes‐Villagrana

Albores-García

Cervantes-Villagrana

et al. 2020

Sig Transduct Target Ther

147

112

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Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1β, CCL2, PGE 2 , among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.

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Section: Classical Central Nervous System Neurotransmitters (Dopaminementioning

confidence: 99%

“…Therefore, inhibition of AKR1C3 and GABA A -R in prostate cancer would hypothetically potentiate conventional therapy. 283…”

Section: Classical Central Nervous System Neurotransmitters (Dopaminementioning

confidence: 99%

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Cervantes‐Villagrana

Albores-García

Cervantes-Villagrana

et al. 2020

Sig Transduct Target Ther

147

112

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“…Further reports demonstrated that non-genomic AR triggered Src-MAPKs-CREB activation [74]. In prostate cancer models, inhibition of Src decreased prostate cancer cell adhesion, migration and invasion, while targeting both Src and Abl (Abelson murine leukaemia viral oncogene homolog) attenuated lymph node metastasis of orthotopic PC3 xenografts [75]. In fact, it was demonstrated the ability of AR to enhance invasion of prostate cancer cell lines, independently of its nuclear localization but in a Src-dependent manner [76].…”

Section: Ar Signalling In Prostate Cancermentioning

confidence: 99%

Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

Amicis

Chimento

Montalto

et al. 2019

IJMS

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Extensive research over the past 25 years in hormone-dependent cancers, such as breast cancer and prostate cancer, has identified the molecular mechanisms driven by steroid receptors, elucidating the interplay between genomic and non-genomic steroid receptors mechanism of action. Altogether, these mechanisms create the specific gene expression programs that contribute to endocrine therapy resistance and cancer progression. These findings, on the bidirectional molecular crosstalk between steroid and growth factor receptors pathways in endocrine resistance, suggest the use of multi-target inhibitors together with endocrine therapies, for treating resistant disease. In this review we will discuss the novel understanding on the chemopreventive and anti-cancer activities of Resveratrol (3,5,4′-trihydroxy-stilbene) (RSV), a phytoalexin found in grapes acting on a plethora of targets. We will highlight Resveratrol effect on steroid receptors signalling and its potential use in the treatment of hormone-dependent cancer. Understanding the molecular mechanisms by which the bioactive compound influences cancer cell behaviour, by interfering with steroid receptors functional activity, will help to advance the design of combination strategies to increase the rate of complete and durable clinical response in patients.

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“…We have recently reported an extensive ion channels expression analysis in several solid tumors demonstrating relevant and significant alterations in bladder cancer, glioblastoma, melanoma, breast cancer, and lung carcinoma, in more than 3000 patients [19], further indicating ion channels as potential therapeutic targets or molecular markers in cancer field. Indeed, ion channels expression has been related to clinical outcome in breast cancer [20] and the role of different ion channels has been recently demonstrated in lung cancer [21,22] as well as prostate cancer [23,24,25]. Mutation in glutamate receptors have been related to increased survival in malignant melanoma [26].…”

Section: Introductionmentioning

confidence: 99%

Ion Channel Expression in Human Melanoma Samples: In Silico Identification and Experimental Validation of Molecular Targets

D’Arcangelo

Scatozza

Giampietri

et al. 2019

Cancers

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Expression of 328 ion channel genes was investigated, by in silico analysis, in 170 human melanoma samples and controls. Ninety-one members of this gene-family (i.e., about 28%) show a significant (p < 0.05) differential expression in melanoma- vs. nevi-biopsies, taken from the GEO database. ROC (receiver operating characteristic) analysis selected 20 genes as potential markers showing the highest discrimination ability of melanoma vs. nevi (AUC > 0.90 and p < 0.0001). These 20 genes underwent a first in silico-validation round in an independent patients-dataset from GEO. A second-in silico-validation step was then carried out on a third human dataset in Oncomine. Finally, five genes were validated, showing extremely high sensitivity and specificity in melanoma detection (>90% in most cases). Such five genes (namely, SCNN1A, GJB3, KCNK7, GJB1, KCNN2) are novel potential melanoma markers or molecular targets, never previously related to melanoma. The “druggable genome” analysis was then carried out. Miconazole, an antifungal drug commonly used in clinics, is known to target KCNN2, the best candidate among the five identified genes. Miconazole was then tested in vitro in proliferation assays; it dose-dependently inhibited proliferation up to 90% and potently induced cell-death in A-375 and SKMEL-28 melanoma cells, while it showed no effect in control cells. Moreover, specific silencing of KCNN2 ion channel was achieved by siRNA transfection; under such condition miconazole strongly increases its anti-proliferative effect. In conclusion, the present study identified five ion channels that can potentially serve as sensitive and specific markers in human melanoma specimens and demonstrates that the antifungal drug miconazole, known to target one of the five identified ion channels, exerts strong and specific anti-melanoma effects in vitro.

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Transition from androgenic to neurosteroidal action of 5α-androstane-3α, 17β-diol through the type A γ-aminobutyric acid receptor in prostate cancer progression

Cited by 13 publications

References 65 publications

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Steroid Receptor Signallings as Targets for Resveratrol Actions in Breast and Prostate Cancer

Ion Channel Expression in Human Melanoma Samples: In Silico Identification and Experimental Validation of Molecular Targets

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