Targeting calcium signaling in cancer therapy.

The calcium signal is a powerful and multifaceted tool by which cells can achieve specific outcomes. Cellular machinery important in tumour progression is often driven or influenced by changes in calcium ions; in some cases this regulation occurs within spatially defined regions. Over the past decade there has been a deeper understanding of how calcium signalling is remodelled in some cancers and the consequences of calcium signalling on key events such as proliferation, invasion and sensitivity to cell death. Specific calcium signalling pathways have also now been identified as playing important roles in the establishment and maintenance of multidrug resistance and the tumour microenvironment.

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The calcium-cancer signalling nexus

Genomic instability is a primary cause and fundamental feature of human cancer. However, all cancer cell genotypes generally translate into several common pathophysiological features, often referre...

https://www.physiology.org/doi/pdf/10.1152/physrev.00044.2016

Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?

Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca2+-selective transient receptor potential (TRP) channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca2+ uptake channels in epithelial tissues. Detailed structural bases for their assembly and Ca2+ permeation remain obscure. Here we report the crystal structure of rat TRPV6 at 3.25 A resolution. The overall architecture of TRPV6 reveals shared and unique features compared with other TRP channels. Intracellular domains engage in extensive interactions to form an intracellular ‘skirt’ involved in allosteric modulation. In the K+ channel-like transmembrane domain, Ca2+ selectivity is determined by direct coordination of Ca2+ by a ring of aspartate side chains in the selectivity filter. On the basis of crystallographically identified cation-binding sites at the pore axis and extracellular vestibule, we propose a Ca2+ permeation mechanism. Our results provide a structural foundation for understanding the regulation of epithelial Ca2+ uptake and its role in pathophysiology. The X-ray crystal structure of rat transient receptor potential channel TRPV6 at 3.25 A resolution is reported, providing new insights into its assembly and calcium-selective permeation. The transient receptor potential (TRP) channels are a superfamily of cation-permeable ion channels that act as transducers of sensory modalities, including temperature, taste, olfaction, vision, hearing and touch. TRPV5 and TRPV6 are TRP channels that are highly selective for Ca2+, and they play vital roles in calcium homeostasis. In this manuscript, the authors report the X-ray crystal structure of rat TRPV6 at 3.25 A resolution. Although the overall architecture of TRPV6 is fairly similar to that of TRPV1, this new structure reveals that exceptionally high Ca2+ selectivity is achieved via the direct coordination of Ca2+ by a ring of aspartate side chains in the selectivity filter. This work provides a structural foundation to understanding the regulation of epithelial Ca2+ uptake and its role in pathophysiology.

Crystal structure of the epithelial calcium channel TRPV6

Plasma membrane calcium channels in cancer: Alterations and consequences for cell proliferation and migration.

Transient receptor potential vanilloid subfamily member 6 (TRPV6) is a highly selective calcium channel that has been considered as a part of store-operated calcium entry (SOCE). Despite its first discovery in the early 2000s, the role of this channel in prostate cancer (PCa) remained, until now, obscure. Here we show that TRPV6 mediates calcium entry, which is highly increased in PCa due to the remodeling mechanism involving the translocation of the TRPV6 channel to the plasma membrane via the Orai1/TRPC1-mediated Ca2+/Annexin I/S100A11 pathway, partially contributing to SOCE. The TRPV6 calcium channel is expressed de novo by the PCa cell to increase its survival by enhancing proliferation and conferring apoptosis resistance. Xenografts in nude mice and bone metastasis models confirmed the remarkable aggressiveness of TRPV6-overexpressing tumors. Immunohistochemical analysis of these demonstrated the increased expression of clinical markers such as Ki-67, prostate specific antigen, synaptophysin, CD31, and CD56, which are strongly associated with a poor prognosis. Thus, the TRPV6 channel acquires its oncogenic potential in PCa due to the remodeling mechanism via the Orai1-mediated Ca2+/Annexin I/S100A11 pathway.

https://www.pnas.org/content/pnas/111/37/E3870.full.pdf

Leonardo Farsetti

Papers

TRPV6 calcium channel translocates to the plasma membrane via Orai1-mediated mechanism and controls cancer cell survival.