Abstract
Advanced prostate cancers that progress to tumor metastases are often considered incurable or difficult to treat. The etiology of prostate cancers is multi-factorial. Among other factors, de-regulation of calcium signals in prostate tumor cells mediates several pathological dysfunctions associated with tumor progression. Calcium plays a relevant role on tumor cell death, proliferation, motility-invasion and tumor metastasis. Calcium controls molecular factors and signaling pathways involved in the development of prostate cancer and its progression. Such factors and pathways include calcium channels and calcium-binding proteins. Nevertheless, the involvement of calcium signaling on prostate cancer predisposition for bone tropism has been relatively unexplored. In this regard, a diversity of mechanisms triggers transient accumulation of intracellular calcium in prostate cancer cells, potentially favoring bone metastases development. New therapies for the treatment of prostate cancer include compounds characterized by potent and specific actions that target calcium channels/transporters or pumps. These novel drugs for prostate cancer treatment encompass calcium-ATPase inhibitors, voltage-gated calcium channel inhibitors, transient receptor potential (TRP) channel regulators or Orai inhibitors. This review details the latest results that have evaluated the relationship between calcium signaling and progression of prostate cancer, as well as potential therapies aiming to modulate calcium signaling in prostate tumor progression.
Highlights
Introduction to Prostate CancerGenetic and environmental factors contribute to alterations of prostate that may lead to uncontrolled cell growth and prostate tumorigenesis and cancer
TRPM8, a calcium permeable channel expressed in the endoplasmic reticulum and the plasma membrane that is experimentally activated in response to cooling and menthol has been described to be needed for the survival of androgen receptor (AR)-dependent LNCaP prostate cancer cells [46]
TRPM8 localization at the endoplasmic reticulum (ER) membrane has been associated with release of calcium from intracellular stores to the cytoplasm leading to increased survival in AR-dependent LNCaP prostate cancer (PCa) cells [46]
Summary
Genetic and environmental factors contribute to alterations of prostate that may lead to uncontrolled cell growth and prostate tumorigenesis and cancer. Many patients with metastatic PCa will develop castrate resistant PCa after 2–3 years, leading to an increase in mortality [4]. The tumors of these patients are considered to be hormone refractory, in the sense that they progress despite a reduction in serum androgens [11]. Tumor cell growth is sustained in castrate resistant PCa by a diversity of mechanisms including intratumoral or adrenal production of androgens, overexpression of AR or mutated AR forms, ligand-independent activation of AR or stabilization of hyper-responsive AR by chaperones (reviewed in [15]). Identification of biomarkers for disease progression and therapeutic targets is considered of the utmost importance
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