Role of Calcium Signaling in Prostate Cancer Progression: Effects on Cancer Hallmarks and Bone Metastatic Mechanisms

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.

Keywords: Calcium; cancer progression; cell signaling; prostate cancer; therapies.

Figure 1

Proposed mechanisms of calcium-dependent apoptosis inhibition in prostate cancer (PCa) cells. Survival signals are induced by calcium entry through transient receptor potential (TRP) TRPM and TRPV channels and Orai 1 and 3 heteromultimers. Elevation of cytoplasmic calcium levels trigger different anti-apoptotic signals including caspase 8 and 9 inhibition by activation of Calcium/Calmodulin-Dependent Kinase II (CAMKII). Alternative mechanisms include inhibition of calcium-dependent mitochodrial apoptosis; excess of intracellular calcium is inhibited by downregulation of Orai homomultimers, of sarco/endoplasmic reticulum calcium ATPase (SERCA) (via cartilage oligomeric matrix protein (COMP) expression) and of IP3R (via COMP1 expression and PTEN (phosphatase and tensin homolog deleted on chromosome 10) channels in PCa cells. Arrows indicate upregulated expression or activity (↑) and downregulated expression or activity (↓). Crosses (X) and ˫ symbol indicate inhibition. Blue filled arrows indicate stimulation. ER: Endoplasmic reticulum. F-box protein XL2: FBXL2.

Figure 2

Proposed mechanisms of calcium-dependent proliferation in prostate cancer (PCa) cells. Upregulation of T-Type Calcium Channels (TTCC) increases the proliferative signals Akt kinase, mammalian target of rapamycin (mTOR), cyclin-dependent kinase 4 (CDK4) and cyclin D1. Transient receptor potential (TRP)V6 (TRPV6) increase proliferation via calcium-dependent activation of Nuclear factor of activated T-cells (NFAT). TRPM4 induces proliferation through activation of calcium-dependent Akt and catenin/Tcf/Lef signaling. Piezo1, TRPC6 and TRPM7 contribute to increased calcium cytosolic levels. Nuclear localization of TRPM2 as well as sarco/endoplasmic reticulum calcium ATPase (SERCA) also promote PCa cell proliferation. Upregulation of muscarinic acetylcholine receptor M3 (CHRM3) induces Akt, glycolysis, lipogenesis, and androgen receptor (AR) re-activation via activation of Calcium/Calmodulin-Dependent Kinase Kinase (CAMKK) causing cell proliferation. Proliferation is also triggered by overactivation of Akt and Extracellular-regulated (ERK) kinases by S100 proteins and by downregulation of regucalcin. Arrows indicate upregulated expression or activity (↑) and downregulated expression or activity (↓). Blue filled arrows indicate stimulation. ER: Endoplasmic reticulum.

Figure 3

Proposed mechanisms of calcium-dependent angiogenesis in prostate cancer (PCa) and endothelial (EC) cells. PCa cells secrete the angiogenic factor VEGF (vascular endotelial growth factor) by increasing intracellular calcium [Ca2+]i via voltage-dependent calcium channel α2δ2 auxiliary subunit overexpression. [Ca2+]i upregulates VEGF through activation of transcription factor Activator protein 1 (AP-1). ECs in the primary prostate tumor induce angiogenic genes by overexpression of S100 proteins. [Ca2+]i upregulation by Transient receptor potential (TRP) TRPC, TRPA and TRPV channels induces proliferation of ECs in prostate primary tumors. Arrows indicate upregulated expression or activity (↑). Blue filled arrows indicate stimulation.

Figure 4

Proposed mechanisms of calcium-dependent Epithelial to Mesenchymal Transition (EMT), migration and invasion in prostate cancer (PCa) cells. Upregulation of intracellular calcium levels dependent on K+ channel (small conductance calcium-activated potassium channel 3) SK3, Transient receptor potential (TRP) and Orai channels overactivate transcription factor Zinc finger E-box-binding homeobox 1 (Zeb1) triggering the expression of EMT genes. EMT genes are also activated by ATP-stimulated P2X7 channel. Invasion of PCa cells is mediated by upregulation of metalloproteases (MMPs) and cathepsin B via TRPV2 and TRPC6-dependent increase of cytosolic calcium levels by a constitutive mechanism. MMPs are also increased by psoriasin. Prostate cell migration is promoted by actin remodeling via calcium receptor (CasR)/calpain/filamin and Wnt5a/Calcium/Calmodulin-Dependent Kinase (CAMK)II pathways. Decreased annexin II and increased Stromal-interacting molecule 1 (STIM1)/Akt kinase activation lead to enhanced cell migration as well. Decreased TRPM8 expression decrease in late stages of androgen-insensitive PCA and is associated with increased cell migration. Arrows indicate upregulated expression or activity (↑) and downregulated expression or activity (↓). Crosses (X) indicate inhibition. Blue filled arrows indicate stimulation. ER: Endoplasmic reticulum.

Figure 5

Proposed mechanisms of calcium-dependent bone colonization in prostate cancer (PCa) cells. Migration to bone and invasion mechanisms are induced by Transient receptor potential V2 TRPV2 and TRPV6-dependent upregulation of cytosolic calcium levels in PCa cells. Adrenomedullin translocates TRPV2 to the membrane triggering migration and invasion mechanisms. Calcitonin induces migration and invasion of PCa cells. Bone osteoblasts transfer calcium to tumor cells via GAP junctions. In turn, cytosolic calcium induces bone colonization by overactivation of NFAT and MEF2 transcription factors and calcium-binding proteins CaMKII and calcineurin. Proliferation of PCa cells in bone is triggered by osteopontin activation of α(v)β3 integrin-dependent upregulation of intracellular calcium levels. PCa cells also secrete the bone resorbing peptide parathyroid hormone-related protein (or PTHrP) inducing receptor activator of nuclear factor-κB (RANK) ligand (RANKL) secretion by osteoblasts. RANKL activates RANK receptor in osteoclasts promoting osteoclast-dependent bone resorption and release of calcium. [Ca2+]o activates the calcium receptor (CasR) in PCa cells triggering cell proliferation via Akt and cyclin D1 activation. Vitamin D antagonizes the effects of high extracellular calcium concentrations on CasR. Arrows indicate upregulated expression or activity (↑) and downregulated expression or activity (↓). Crosses (X) and ˫ symbol indicate inhibition. Blue filled arrows indicate stimulation.