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Ca2+ Signaling in metastasis: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Jeong Hee Hong.

Intracellular Ca2+ signaling is a critical factor in breast cancer metastasis. In the proliferation stage, increases in intracellular Ca2+ concentration through voltage-dependent Ca2+ channels, P2Y2 channels, transient receptor potential (TRP) channels, store-operated Ca2+ channels (SOCCs), and IP3 receptors and a decrease in intracellular Ca2+ concentration through plasma membrane Ca2+ ATPases and secretory pathway Ca2+ ATPases (SPCA) activate breast cancer cell proliferation. TRPM7, SOCC, inositol trisphosphate receptor (IP3R), ryanodine receptor (RyR), and sarco-/endo-plasmic reticulum Ca2+-ATPase (SERCA) increase the expression of epithelial-to-mesenchymal transition (EMT)-related proteins; meanwhile, SPCA and the Na+/Ca2+ exchanger (NCX) control the activation of EMT-related proteins. Increased Ca2+ through TRPC1, TRPM7/8, P2X7, and SOCC enhances breast cancer cell migration. The stromal interaction molecule (STIM)-Orai complex, P2X7, and Ca2+ sensing receptors are involved in invadopodia. Various pharmacological agents for Ca2+ channels have been proposed against breast cancer and have provided potential strategies for treating metastatic processes.

  • Ca2+ channels
  • breast cancer
  • Ca2+ signaling
  • brain metastasis

1. Introduction

Cancer metastasis occurs in several stages, including proliferation, epithelial-to-mesenchymal transition (EMT), invasion, transport, colonization, and angiogenesis (Figure 1) [1]. In fully developed tumorigenesis stages, circulating tumor cells move into another tissue and transform into mesenchymal stem cell-like cells as a result of EMT [2][3]. EMT is the initiation step in cancer metastasis [4]. Tumor cells are transported through the bloodstream after invading blood vessels [5][6][7] in a process called intravasation [8]. The metastasized tumor cells attach and grow via colonization; then, the blood vessels that supply nutrients are generated during angiogenesis, leading to cancer development [2][9][10]. In many stages of metastasis, the proteins and factors related to metastasis are intricate [11]. Therefore, messenger signaling to block metastasis and tumorigenesis is necessary for the fundamental processes that regulate initial signaling factors, but protein signaling is not. Breast cancer is the most common cancer type, and it has been considered one of the most malignant cancers in women worldwide [12][13]. Breast cancer subtypes include triple-negative and triple-positive breast cancer resulting from the existence and nonexistence of estrogen receptors, progesterone receptors, or human epidermal growth factor receptor-2 (HER2) [14][15]. Each subtype has the following cell lines: triple-negative (MDA-MB-231, MDA-MB-486, and MCF-10A [16][17]), triple-positive (BSMZ, BT474, and EFM192A [16]), and hormone receptor-positive cell lines that express estrogen receptors and progesterone receptors in the absence of HER2 (MCF-7 and T47D [16]). Genotypic or phenotypic heterogeneity of breast cancer is diverse. While triple-negative breast cancer generally has the most aggressive behavior and poor clinical outcomes [18][19][20], triple-positive breast cancer has also been found to exhibit aggressive behavior, despite the availability of antibody-targeted therapy or chemotherapy [21].

Figure 1. The metastatic pathway of breast cancer cells. Proliferated breast cancer cells are transformed into mesenchymal-like cells and undergo invasion and intravasation to blood vessels. Transporting tumor cells perform extravasation from blood vessels and generate a cancerous environment through colonization and angiogenesis.

2. The Pharmacological Application of Ca2+ Signaling Blockers to Breast Cancer

Various attempts to use antagonists of Ca2+ channels have been proposed to control breast cancer tumorigenesis. The mediation of [Ca2+]i signaling is critical for cellular functions regardless of the cellular type (tumor vs. nontumor). In other words, the application of Ca2+ signaling blockers for anticancer drugs requires in-depth studies of the basic mechanisms underlying Ca2+ signaling and cancer cells. Thus, we summarized the studies that have used Ca2+ channel blockers for breast cancer medication to understand the associated mechanisms (Table 1). Recent studies have shown that the L-type Ca2+ channel blockers amlodipine, diltiazem, and verapamil have been used to modulate high blood pressure [22][23][24] and attenuate HT39-transplanted breast cancer growth [25]. Mice with increased Ca2+ concentration in serum exhibit a larger amount of HT39 tumor tissue, while treatment with amlodipine attenuates Ca2+ signaling in HT39 cells with a decrease in tumor size [25]. The T-type Ca2+ channel blockers mibefradil (another hypertension drug [26]) and pimozide (chronic psychosis drug [27]) inhibit MCF-7 breast cancer cell growth by inhibiting T-type Ca2+ current; furthermore, combined treatment with pimozide and mibefradil shows synergistic effects on cell growth in MCF-7 cells, decreasing cell growth [28].

TRP channels are prominent in breast cancer. Among these, TRPM channels are considered therapeutic targets for antagonists. The TRPM7 inhibitor 2-aminoethyl diphenylborinate (2-APB [29]) attenuates MDA-MB-231, AU565, and T47D cell proliferation, increasing S phase and decreasing G0/G1 phase in the breast cancer cell cycle [30]. Moreover, TRPM7-silenced MDA-MB-231 cells have no antitumor effects when 2-APB is administered [30]. Treatment with the antifungal agent clotrimazole, which inhibits TRPM2 activity [31], decreases MDA-MB-231 cell invasion, which is accompanied by apoptosis and G1-phase arrest [32]. Clotrimazole increases cleaved poly (ADP-ribose) polymerase (PARP), cleaved caspase-3, and B-cell lymphoma-2 (Bcl-2)-associated X expression, which induces apoptotic signaling in MDA-MB-231 cells [32]. Inhibition of Ca2+ signaling with the voltage-independent Ca2+ channel inhibitor carboxyamidotriazole reduces MCF-7 proliferation by arresting G2/M phase cell cycle, decreasing BCL-2 (which blocks apoptotic signaling) expression, and increasing p21 expression, which induces apoptotic signaling [33]. Furthermore, treatment with carboxyamidotriazole reduces mitochondrial membrane potential [33], which is highly activated in cancer stem cells to produce reactive oxygen species (ROS) [34]. In addition, administration of the SERCA inhibitor thapsigargin inhibits S100A4 protein expression in MDA-MB-231 breast cancer cells [35].

Table 1. The Ca2+ channel blockers with potential anticancer effects.

Reagents Description Effect Ref.
Amlodipine Medication for high blood pressure and L-type Ca2+ channel inhibitor Decrease of HT39-transplanted breast cancer growth [25]
Diltiazem
Verapamil
Mibefradil Hypertension drug Decrease of MCF-7 growth through inhibition of T-type Ca2+ current [26]
Pimozide Chronic psychosis drug [27]
2-APB TRPM7 inhibitor Decrease of MDA-MB-231, AU565, and T47D cell growth through pausing cell cycle [30]
Clotrimazole TRPM2 inhibitor Decrease of MDA-MB-231 cell growth through G1-phase arrest [32]
Carboxyamidotriazole Reduce mitochondrial membrane potential Attenuation of ROS [34]
Thapsigargin SERCA inhibitor Inhibition of S100A4 expression in MDA-MB-231 [35]

In addition, Ca2+ channel blockers enhance the therapeutic effect of traditional drugs or overcome resistance to insignificant drugs. In an attempt to improve their therapeutic effect on breast cancer, mibefradil enhanced the apoptotic effect of the anticancer drug 2-deoxy-D-glucose (2-DG) by arresting the cell cycle in MDA-MB-231 cells [36]. Furthermore, clotrimazole increases the inhibitory effect of imatinib mesylate on T74D cells to mediate kinase inhibition [37]. Mibefradil is a T-type Ca2+ channel blocker that arrests the cell cycle at the G1 phase and evaluates glucose metabolism [36]. The application of only 2-DG also inhibits MDA-MB-231 cell growth. Although the inhibition rate is very low (approximately 10%), the combination of mibefradil and 2-DG leads to a synergistic antitumor effect (approximately 30% of inhibition rate) [36]. The combination of imatinib mesylate and clotrimazole synergistically decreases T74D cell growth by increasing lactate dehydrogenase and nitric oxide leakage [36], which induces membrane damage and apoptosis in cancer cells [38][39]. Doxorubicin and daunorubicin are the most well-known anthracycline antibiotics and are also first-line drugs for malignancies [40]. They have structural features that can be intercalated into DNA bases and inhibit topo ii/DNA ternary complexes [41]. Additionally, the quinone ring, a common structure for anthracyclines such as doxorubicin and daunorubicin, induces ROS production [42][43][44][45]. Doxorubicin and daunorubicin are typical anticancer reagents; however, they are hindered by multidrug resistance in breast cancer [46][47]. The addition of diltiazem to doxorubicin-treated MCF-7 cells increases the expression of apoptosis-related p53 genes [46]. The combination of daunorubicin and amlodipine reportedly predominantly attenuates tumor volume in the MCF-7 xenograft tumor model via mitochondrial destruction [47]. Despite these applicable combinations, more studies on effective combinations of Ca2+ channel blockers and traditional anticancer drugs should be conducted. These combined treatments are suggested as novel therapeutic strategies against breast cancer and breast-to-brain metastatic cancer.

As mentioned above, Ca2+ channel blockers have pharmacological potential. However, the therapeutic application of Ca2+ channel blockers is challenging, as each reagent does not act on a single channel or transporter. The TRPM7 inhibitor 2-APB inhibits IP3R [48], Orai1/2-induced SOCE [49], and other TRP channels [50]. In contrast, 2-APB induces Orai3-induced Ca2+ influx [49]. Additionally, the Ca2+ channel blocker clotrimazole can inhibit Ca2+-activated potassium channel 3.1 [51], which drives Ca2+ through SOCE [52]. Although several Ca2+ channel blockers are pharmacologically complicated to use as therapeutic strategies, the specific mechanisms of Ca2+ channel blockers need to be clarified.

3. Future Perspective

The relationship between Ca2+ channels and breast cancer has been assessed for several decades; however, the effect of Ca2+ channels on the metastasis of breast cancer to the brain requires further investigation. The treatment of breast cancer by modulating Ca2+ channel expression and its activity has been considered a cancer therapeutic strategy using various Ca2+ channel blockers. Although Ca2+ signaling is closely related to cancer metastasis in various organs, the application of Ca2+ channel modulation for breast cancer metastasis has not been sufficiently studied. Based on the scope of metastatic breast cancer in this review, several studies have shown that Ca2+ channels have the potential to control metastatic stages and the movement of metastatic breast cancer cells to the brain by modulating adhesive function and permeability. Over the past several years, the number of cases of brain metastases from breast cancer has increased, and the entire metastatic process has not been fully elucidated. In addition, other metastatic processes should be highlighted beyond adhesive and invasive processes. For example, cellular-secreted processes and gene transcription activities are associated with Ca2+ signaling. In other words, communication between cancer cells and other tissues will commence with the untact mode, such as cytokine release. This mode builds up prior to the contact mode, which includes adhesion. Ca2+ is an attractive source of the untact mode for transferring the on-mode of metastatic signals through simple mobilization from abundant sources. Therefore, blocking Ca2+ channels as gatekeepers and modulating Ca2+ signaling can be attractive candidates for therapeutic approaches, and suitable combination therapies are suggested as relevant options for metastatic breast cancer therapy.

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