Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

Abstract

Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them to signaling hubs needing the cations. Ca2+ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca2+ repositories. Cellular Ca2+ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca2+ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca2+ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca2+ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area.

Identification of microsatellite instability and immune-related prognostic biomarkers in colon adenocarcinoma

“…CALB2 (Calbindin 2) encodes an intracellular calciumbinding protein belonging to the troponin C superfamily. This protein plays an important role in message targeting and intracellular calcium buffering and related to cancer progression (47)(48)(49). Among DEGs of MSI-H and MSI-L subtypes, CALB2 has the highest fold change.…”

Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma?

“…Another more notable factor that should be considered is the underlying roles of other intra-membrane proteins that regulate flow of free Ca 2+ between organelles and the cytoplasm, such as inositol 1,4,5-triphosphate receptor (IP 3 R) and transient receptor potential (TRP) channels. IP 3 R regulates the release of ER calcium stores, while TRP channels are primarily involved in Ca 2+ influx through the plasma membrane [ 210 ]. Therefore, these channels may directly contribute to the activation of ANOs.…”

“…TRP channels are a superfamily of 30 cationic cell membrane channels that are permeable to Ca 2+ and directly activate intracellular Ca 2+ signalling [ 210 ]. TRPC (TRP canonical) and TRPV (TRP vanilloid) are the two TRP channel subfamilies most commonly implicated in GBM [ 218 ].…”

“…TRPV4 is upregulated in glioma, positively correlates with tumour grade in glioma patients, and is associated with a worse prognosis [ 231 , 232 , 233 ]. TRPV4 is another potential binding partner for EGFR [ 210 , 234 , 235 ], ANO1 [ 236 , 237 ], and IP3R [ 237 ], although this has yet to be demonstrated in brain cancer cells. Nonetheless, it has been shown that TRPV4 promotes glioma cell migration and invasion through Akt signalling and regulating the formation of cellular protrusions [ 231 , 233 ].…”

The role of Ca2+ in the injury of host cells during the schizogenic stage of E. tenella

“…It is the most common and important signal transduction component in cells that acts as a second messenger together with cyclic adenosine monophosphate ( cAMP ) ( Lock and Parker, 2020 ). Studies have shown that Ca 2+ plays an important role in causing fatal damage to cells ( Sharma et al, 2021 ). Ca 2+ overload is the "last common pathway" for cell damage caused by many reasons.…”