Regucalcin Is a Potential Regulator in Human Cancer: Aiming to Expand into Cancer Therapy

Abstract

Regucalcin, a calcium-binding protein lacking the EF-hand motif, was initially discovered in 1978. Its name is indicative of its function in calcium signaling regulation. The rgn gene encodes for regucalcin and is situated on the X chromosome in both humans and vertebrates. Regucalcin regulates pivotal enzymes involved in signal transduction and has an inhibitory function, which includes protein kinases, protein phosphatases, cysteinyl protease, nitric oxide dynthetase, aminoacyl-transfer ribonucleic acid (tRNA) synthetase, and protein synthesis. This cytoplasmic protein is transported to the nucleus where it regulates deoxyribonucleic acid and RNA synthesis as well as gene expression. Overexpression of regucalcin inhibits proliferation in both normal and cancer cells in vitro, independent of apoptosis. During liver regeneration in vivo, endogenous regucalcin suppresses cell growth when overexpressed. Regucalcin mRNA and protein expressions are significantly downregulated in tumor tissues of patients with various types of cancers. Patients exhibiting upregulated regucalcin in tumor tissue have shown prolonged survival. The decrease of regucalcin expression is linked to the advancement of cancer. Overexpression of regucalcin carries the potential for preventing and treating carcinogenesis. Additionally, extracellular regucalcin has displayed control over various types of human cancer cells. Regucalcin may hold a prominent role as a regulatory factor in cancer development. Supplying the regucalcin gene could prove to be a valuable asset in cancer treatment. The therapeutic value of regucalcin suggests its potential significance in treating cancer patients. This review delves into the most recent research on the regulatory role of regucalcin in human cancer development, providing a novel approach for treatment.

Keywords: cancer suppressor; carcinogenesis; cell proliferation; cell signaling; gene therapy; regucalcin.

Figure 1

The expression of regucalcin is regulated by various signaling factors implicated in the action of peptide hormones, steroid hormones, and other factors. The transcription factors AP-1, NF1-A1, RGPR-p117, and others are involved in the expression of the regucalcin gene. These transcription factors are transported from the cytoplasm to the nucleus through a mechanism mediated via intracellular signaling factors. These signaling factors include cyclic AMP-dependent protein kinase (A kinase), Ca²⁺-calmodulin-dependent protein kinase (CaM kinase), and protein kinase C (C kinase). These factors are coupled to the signaling processes of various factors. Steroid hormones directly bind to receptors in the cytoplasm and nucleus, increasing the expression of the regucalcin gene through transcription factors. Additionally, the promoter activity of the regucalcin gene is enhanced in the nucleus.

Figure 2

Regucalcin inhibits proliferation in various types of normal and cancer cells. Within cells, intracellular regucalcin reduces the activity of several enzymes involved in signaling, such as Ca²⁺/calmodulin-dependent enzymes, protein kinases, and protein phosphatases in the cytoplasm. Additionally, regucalcin activates cysteinyl protease and aminoacyl-tRNA synthetase, leading to a decrease in protein production. Cytoplasmic regucalcin is translocated to the nucleus through protein kinase-related signaling. Nuclear regucalcin inhibits both Ca²⁺-dependent and -independent protein kinase and protein phosphatase, and suppresses nuclear DNA and RNA synthesis. Overexpressed regucalcin obstructs the G1 and G2/M phases of the cell cycle. Therefore, regucalcin’s suppression of cell proliferation occurs by regulating various signaling processes. The black upward arrow signifies upregulation, while the black and red downward arrows denote downregulation.

Figure 3

Regucalcin may have a role in suppressing human cancer. Low expression levels of the regucalcin gene and protein seem to be associated with unfavorable outcomes in patients with various types of human cancer. The patients were divided into two groups based on their regucalcin gene expression, high and low. The high regucalcin gene expression group exhibited a statistically significant difference (p-value) compared to the low group. The Kaplan-Meier curve showed a significant increase in the survival rate of cancer patients in the high regucalcin gene expression group compared to the low expression group. Abbreviations: RGN, regucalcin.

Figure 3

Regucalcin may have a role in suppressing human cancer. Low expression levels of the regucalcin gene and protein seem to be associated with unfavorable outcomes in patients with various types of human cancer. The patients were divided into two groups based on their regucalcin gene expression, high and low. The high regucalcin gene expression group exhibited a statistically significant difference (p-value) compared to the low group. The Kaplan-Meier curve showed a significant increase in the survival rate of cancer patients in the high regucalcin gene expression group compared to the low expression group. Abbreviations: RGN, regucalcin.

Figure 4

The underlying mechanism by which extracellular regucalcin suppresses the proliferation of human cancer cells in vitro. Extracellular regucalcin blocks various EGF-related signaling pathways by targeting EGF receptors in cells. In addition, extracellular regucalcin may bind to putative regucalcin-binding sites on plasma membranes to transmit signals to cells. In addition, intracellular regucalcin may suppress other signaling processes and the levels of transcription factors. In particular, extracellular regucalcin increases the levels of p53, Rb, and p21, which are suppressors of tumorigenesis, suggesting an effect on nuclear function. Extracellular regucalcin may affect various molecules in cancer cells, leading to the promotion of tumorigenesis. Extracellular regucalcin may play a critical role as a suppressor in the cancer microenvironment. Abbreviations: RGN; regucalcin; EGF; epidermal growth factor. The black down arrow indicates downregulation. The blue down arrow indicates downregulation.

Figure 5

The role of regucalcin in the development and management of human cancer is examined. The expression of the regucalcin gene is influenced by different factors, such as hormonal, nutritional, and chemical factors. Altered regucalcin gene expression can cause various metabolic disorders, leading to uncontrolled cell proliferation, tumorigenesis, and metastasis. This process can be blocked by increasing the levels of regucalcin. Preventive and therapeutic efficacy of cancer can be brought by increasing regucalcin levels in tissues and cells through epigenetic modification, nutritional factors, and natural chemical treatment. Abbreviations: RGN; regucalcin. The red down arrow indicates downregulation. The blue up arrow indicates upregulation.