Thyroid Hormone Signalling in Human Evolution and Disease: A Novel Hypothesis

Thyroid hormone (TH) signalling is a universally conserved pathway with pleiotropic actions that is able to control the development, metabolism, and homeostasis of organisms. Using evidence from paleoecology/palaeoanthropology and data from the physiology of modern humans, we try to assess the natural history of TH signalling and its role in human evolution. Our net thesis is that TH signalling has likely played a critical role in human evolution by facilitating the adaptive responses of early hominids to unprecedently challenging and continuously changing environments. These ancient roles have been conserved in modern humans, in whom TH signalling still responds to and regulates adaptations to present-day environmental and pathophysiological stresses, thus making it a promising therapeutic target.

With an Ear up Against the Wall: An Update on Mechanoperception in Arabidopsis.

Cells interpret mechanical signals and adjust their physiology or development appropriately. In plants, the interface with the outside world is the cell wall, a structure that forms a continuum with the plasma membrane and the cytoskeleton. Mechanical stress from cell wall damage or deformation is interpreted to elicit compensatory responses, hormone signalling, or immune responses. Our understanding of how this is achieved is still evolving; however, we can refer to examples from animals and yeast where more of the details have been worked out. Here, we provide an update on this changing story with a focus on candidate mechanosensitive channels and plasma membrane-localized receptors.

Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer

Breast and prostate cancer are the second and third leading causes of death amongst all cancer types, respectively. Pathogenesis of these malignancies is characterised by dysregulation of sex hormone signalling pathways, mediated by the estrogen receptor-α (ER) in breast cancer and androgen receptor (AR) in prostate cancer. ER and AR are transcription factors whose aberrant function drives oncogenic transcriptional programs to promote cancer growth and progression. While ER/AR are known to stimulate cell growth and survival by modulating gene transcription, emerging findings indicate that their effects in neoplasia are also mediated by dysregulation of protein synthesis (i.e., mRNA translation). This suggests that ER/AR can coordinately perturb both transcriptional and translational programs, resulting in the establishment of proteomes that promote malignancy. In this review, we will discuss relatively understudied aspects of ER and AR activity in regulating protein synthesis as well as the potential of targeting mRNA translation in breast and prostate cancer.

Leptin antagonism inhibits prostate cancer xenograft growth and progression

Hyperleptinaemia is a well-established therapeutic side effect of drugs inhibiting the androgen axis in prostate cancer (PCa), including main stay androgen deprivation therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark pathways, including growth, proliferation, migration, angiogenesis, metabolism and inflammation, targeting the leptin axis is therapeutically appealing, especially in advanced PCa where current therapies fail to be curative. In this study, we uncover leptin as a novel universal target in PCa and are the first to highlight increased intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patients' tumours exposed to androgen deprivation, as is observed in patients' tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal the world-first preclinical evidence that demonstrates marked efficacy of targeted leptin-signalling blockade, using Allo-aca, a potent, specific, and safe LEPR peptide antagonist. Allo-aca-suppressed tumour growth and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour vascularity and altered pathways of apoptosis, transcription/translation, and energetics in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We highlight LEPR blockade in combination with androgen axis inhibition represents a promising new therapeutic strategy vital in advanced PCa treatment.

Regulation of ecdysone production in Drosophila by neuropeptides and peptide hormones

In both mammals and insects, steroid hormones play a major role in directing the animal's progression through developmental stages. To maximize fitness outcomes, steroid hormone production is regulated by the environmental conditions experienced by the animal. In insects, the steroid hormone ecdysone mediates transitions between developmental stages and is regulated in response to environmental factors such as nutrition. These environmental signals are communicated to the ecdysone-producing gland via the action of neuropeptide and peptide hormone signalling pathways. While some of these pathways have been well characterized, there is evidence to suggest more signalling pathways than has previously been thought function to control ecdysone production, potentially in response to a greater range of environmental conditions. Here, we review the neuropeptide and peptide hormone signalling pathways known to regulate the production of ecdysone in the model genetic insect Drosophila melanogaster , as well as what is known regarding the environmental signals that trigger these pathways. Areas for future research are highlighted that can further contribute to our overall understanding of the complex orchestration of environmental, physiological and developmental cues that together produce a functioning adult organism.

Pigment Epithelium-Derived Factor and Sex Hormone-Responsive Cancers

Oestrogens and androgens play important roles in normal and cancerous tissue and have been shown to negatively regulate pigment epithelium-derived factor (PEDF) expression in sex hormone-responsive tumours. PEDF suppresses tumour growth and its downregulation by oestrogen is implicated in tumorigenesis, metastasis, and progression. PEDF expression is reduced in cancerous tissue of the prostate, breast, ovary, and endometrium compared to their normal tissue counterparts, with a link between PEDF downregulation and sex hormone signalling observed in pre-clinical studies. PEDF reduces growth and metastasis of tumour cells by promoting apoptosis, inhibiting angiogenesis, increasing adhesion, and reducing migration. PEDF may also prevent treatment resistance in some cancers by downregulating oestrogen receptor signalling. By interacting with components of the tumour microenvironment, PEDF counteracts the proliferative and immunosuppressive effects of oestrogens, to ultimately reduce tumorigenesis and metastasis. In this review, we focus on sex hormone regulation of PEDF’s anti-tumour action in sex hormone-responsive tumours.