Abstract
BackgroundProstate cancer is a major contributor to mortality worldwide, and significant efforts are being undertaken to decipher specific cellular and molecular pathways underlying the disease. Chronic stress is known to suppress reproductive function and promote tumor progression in several cancer models, but our understanding of the mechanisms through which stress contributes to cancer development and progression is incomplete. We therefore examined the relationship between stress, modulation of the gonadotropin-releasing hormone (GnRH) system, and changes in the expression of cancer-related genes in the rat prostate.MethodsAdult male rats were acutely or repeatedly exposed to restraint stress, and compared to unstressed controls and groups that were allowed 14 days of recovery from the stress. Prostate tissue was collected and frozen for gene expression analyses by PCR array before the rats were transcardially perfused; and brain tissues harvested and immunohistochemically stained for Fos to determine neuronal activation.ResultsAcute stress elevated Fos expression in the paraventricular nucleus of the hypothalamus (PVH), an effect that habituated with repeated stress exposure. Data from the PCR arrays showed that repeated stress significantly increases the transcript levels of several genes associated with cellular proliferation, including proto-oncogenes. Data from another array platform showed that both acute and repeated stress can induce significant changes in metastatic gene expression. The functional diversity of genes with altered expression, which includes transcription factors, growth factor receptors, apoptotic genes, and extracellular matrix components, suggests that stress is able to induce aberrant changes in pathways that are deregulated in prostate cancer.ConclusionsOur findings further support the notion that stress can affect cancer outcomes, perhaps by interfering with neuroendocrine mechanisms involved in the control of reproduction.
Highlights
Prostate cancer is a major contributor to mortality worldwide, and significant efforts are being undertaken to decipher specific cellular and molecular pathways underlying the disease
We aimed to determine if chronic stress modulates hypothalamic gonadotropin-releasing hormone (GnRH) and affects the expression of genes associated with prostate cell proliferation, and if recovery from stress could induce a rebound of GnRH release that subsequently contributes to an upregulation of genes that promote metastasis
Effects of restraint stress on hypothalamic neuroendocrine pathways Brain tissue sections containing the paraventricular nucleus of the hypothalamus (PVH) were immunohistochemically stained for Fos as a marker of neuronal activation following restraint stress and recovery
Summary
Prostate cancer is a major contributor to mortality worldwide, and significant efforts are being undertaken to decipher specific cellular and molecular pathways underlying the disease. One of the physiological systems that becomes activated during stress is the hypothalamic-pituitaryadrenal (HPA) axis. Activation of the HPA axis triggers the release of corticotrophin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus (PVH) which, in turn, induces the anterior pituitary to secrete adrenocorticotropic hormone (ACTH), resulting in the production of cortisol by the adrenal cortex. The entire axis is regulated via negative feedback provided by cortisol at the hypothalamic and pituitary levels [2]. Chronic stress can adversely alter hormone levels, affecting the regulation of the stress response which can have a negative effect on the overall physiology of the body [3, 4]. Stress can have deleterious effects on health, contributing to the incidence and progression of diseases such as cancer
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