Role of the calcium-sensing receptor (CaSR) in cancer metastasis to bone: Identifying a potential therapeutic target

Tuffour, Alex; Kosiba, Anthony Adebayiga; Zhang, Yao; Peprah, Frank Addai; Gu, Jie; Shi, Haifeng

doi:10.1016/j.bbcan.2021.188528

Cited by 15 publications

(10 citation statements)

References 103 publications

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“…What is more important, CaSR has been reported to play a critical role in either promoting or suppressing the progression of several human cancers [ 35 , 40 ]. For example, CaSR overexpression in breast, lung, prostate and kidney cancers were positively correlated with tumor progression and shorter survival; inhibition or silence of CaSR markedly suppressed cancer cell proliferation, invasion, and migration [ 26 , 41 ]. Mechanistic studies have suggested that CaSR promotes tumor growth and metastasis through regulating multiply signaling pathways, such as PLC-PKC, MEK-ERK and PI3K-Akt pathways [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

et al. 2022

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Background Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism. Methods Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, β-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells. Results Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent β-catenin stabilization and nuclear translocation. Nuclear β-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells. Conclusions This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma.

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Section: Discussionmentioning

confidence: 99%

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

et al. 2022

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“…It has been known that CaSR controls Ca 2+ homeostasis through its modulation of the parathyroid glands and kidneys, therefore contributing to chondrocytes, osteoblasts, and osteoclasts differentiation, leading to skeletal development and bone turnover [ 116 ]. Moreover, the role of extracellular Ca 2+ and CaSR in cancers has been identified, promoting tumor cell proliferation, migration, and bone metastasis [ 117 ]. Another study showed a high CaSR expression in RCC, and high extracellular Ca 2+ levels enhanced migratory potential and proliferation of bone metastasizing primary RCC cells [ 118 ].…”

Section: Casrmentioning

confidence: 99%

Roles of calcium signaling in cancer metastasis to bone

Xie

Chen

Jiang

et al. 2022

Exploration of Targeted Anti-Tumor Therapy

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Bone metastasis is a frequent complication for cancers and an important reason for the mortality in cancer patients. After surviving in bone, cancer cells can cause severe pain, life-threatening hypercalcemia, pathologic fractures, spinal cord compression, and even death. However, the underlying mechanisms of bone metastasis were not clear. The role of calcium (Ca2+) in cancer cell proliferation, migration, and invasion has been well established. Interestingly, emerging evidence indicates that Ca2+ signaling played a key role in bone metastasis, for it not only promotes cancer progression but also mediates osteoclasts and osteoblasts differentiation. Therefore, Ca2+ signaling has emerged as a novel therapeutical target for cancer bone metastasis treatments. Here, the role of Ca2+ channels and Ca2+-binding proteins including calmodulin and Ca2+-sensing receptor in bone metastasis, and the perspective of anti-cancer bone metastasis therapeutics via targeting the Ca2+ signaling pathway are summarized.

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“…The calcium-sensing receptor (CaSR) works as a key regulator by sensing extracellular Ca 2+ fluctuations to affect downstream intracellular signaling pathways ( Tuffour et al, 2021 ). Thus, CaSR plays a key role in maintaining cellular Ca 2+ homeostasis.…”

Section: Roles Of Class C G Protein-coupled Receptors In Cochleamentioning

confidence: 99%

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

Guo²,

Fu³

et al. 2022

Front. Mol. Neurosci.

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The prevalence of hearing loss-related diseases caused by different factors is increasing worldwide year by year. Currently, however, the patient’s hearing loss has not been effectively improved. Therefore, there is an urgent need to adopt new treatment measures and treatment techniques to help improve the therapeutic effect of hearing loss. G protein-coupled receptors (GPCRs), as crucial cell surface receptors, can widely participate in different physiological and pathological processes, particularly play an essential role in many disease occurrences and be served as promising therapeutic targets. However, no specific drugs on the market have been found to target the GPCRs of the cochlea. Interestingly, many recent studies have demonstrated that GPCRs can participate in various pathogenic process related to hearing loss in the cochlea including heredity, noise, ototoxic drugs, cochlear structure, and so on. In this review, we comprehensively summarize the functions of 53 GPCRs known in the cochlea and their relationships with hearing loss, and highlight the recent advances of new techniques used in cochlear study including cryo-EM, AI, GPCR drug screening, gene therapy vectors, and CRISPR editing technology, as well as discuss in depth the future direction of novel GPCR-based drug development and gene therapy for cochlear hearing loss. Collectively, this review is to facilitate basic and (pre-) clinical research in this area, and provide beneficial help for emerging GPCR-based cochlear therapies.

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Role of the calcium-sensing receptor (CaSR) in cancer metastasis to bone: Identifying a potential therapeutic target

Cited by 15 publications

References 103 publications

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

Roles of calcium signaling in cancer metastasis to bone

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

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