5 research outputs found
Extreme Activation of Androgen Receptor for Prostate Cancer Therapy
Prostate cancer (PCa) is the second most common cancer worldwide in men and one of the major causes of cancer-related death among men in Australia. In PCa cells, the androgen receptor (AR) is the key driver of cell proliferation, cell cycle progression, and metabolism; thus, blocking AR activity with androgen deprivation therapy (ADT) is a standard-of-care treatment for metastatic PCa. However, ADT is never curative, with all patients eventually relapsing with lethal castration-resistant prostate cancer (CRPC). In a paradoxical phenomenon, potent activation of AR with high doses of androgens can also inhibit the growth of PCa tumours. However, the exact mechanism(s) by which activation of AR can block PCa growth is poorly understood. Therefore, in my PhD project, I explored the mechanisms underlying PCa growth suppression in response to extreme activation of AR using a potent androgen, methyltestosterone (MeT). I have found that methyl-testosterone (MeT), a synthetic androgen, can potently transactivate AR and suppress the proliferation of AR-positive prostate cancer cells (LNCaP, C42B, MR49F, and 22RV1) but not an AR-negative cell line (PC3) or a PCa model expressing a version of the AR lacking the ligand-binding domain (R1-D567), suggesting that the growth-inhibitory effects of MeT are AR-dependent. Mechanistically, MeT acts much like high-dose dihydrotestosterone (DHT) in terms of genome-wide AR binding (evaluated by ChIP-seq) and the transcriptional program activated via AR (evaluated by RNA-seq). However, these analyses showed that MeT only extends the AR cistrome and enables AR to act as a potent transcriptional repressor of genes associated with cell cycle, DNA replication, and DNA damage responses. Unexpectedly, our RNA-seq data revealed that MeT dysregulates the expression of transposable elements, including endogenous retroviruses (ERVs). Mechanistically, we found that MeT suppresses the expression of DNA methyl-transferases (DNMTs) and EZH2, which are considered to be key factors repressing the expression of transposable elements. Consistent with the proposed hypothesis, my PhD work showed that MeT caused global hypomethylation of DNA and re-distribution of H3K27me3. More specifically, my research supports a model whereby DNA hypomethylation was linked to the induction of endogenous retroviruses (ERVs). Interestingly, I found that ERV induction was associated with a “viral mimicry” response characterised by activation of pattern recognition receptors RIG-I and STING and subsequent activation of interferon (IFN) signalling. Importantly, I also observed increased expression of MHC class I genes with MeT treatment, suggesting that it can enhance tumour immunogenicity. Validating this finding, co-culture of a murine model of PCa (RM1) with tumour-specific CD8+ T cells revealed that MeT promoted enhanced recognition and functional cytokine production by T cells. Collectively, my work has provided a greater understanding of growth-inhibitory effects of androgens on PCa tumours and uncovers a potential new role for high-dose androgen therapy as an immunosensitisation agent.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202
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Recent advances on biomedical applications of scaffolds in wound healing and dermal tissue engineering.
The tissue engineering field has developed in response to the shortcomings related to the replacement of the tissues lost to disease or trauma: donor tissue rejection, chronic inflammation and donor tissue shortages. The driving force behind the tissue engineering is to avoid the mentioned issues by creating the biological substitutes capable of replacing the damaged tissue. This is done by combining the scaffolds, cells and signals in order to create the living, physiological, three-dimensional tissues. A wide variety of skin substitutes are used in the treatment of full-thickness injuries. Substitutes made from skin can harbour the latent viruses, and artificial skin grafts can heal with the extensive scarring, failing to regenerate structures such as glands, nerves and hair follicles. New and practical skin scaffold materials remain to be developed. The current article describes the important information about wound healing scaffolds. The scaffold types which were used in these fields were classified according to the accepted guideline of the biological medicine. Moreover, the present article gave the brief overview on the fundamentals of the tissue engineering, biodegradable polymer properties and their application in skin wound healing. Also, the present review discusses the type of the tissue engineered skin substitutes and modern wound dressings which promote the wound healing
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Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer.
UNLABELLED: Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a "viral mimicry" response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8+ T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies. SIGNIFICANCE: Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies