Calcium is an important second messenger involved in intra- and extracellular signaling cascades and plays an essential role in cell life and death decisions. The Ca(2+) signaling network works in many different ways to regulate cellular processes that function over a wide dynamic range due to the action of buffers, pumps and exchangers on the plasma membrane as well as in internal stores. Calcium signaling pathways interact with other cellular signaling systems such as reactive oxygen species (ROS). Although initially considered to be potentially detrimental byproducts of aerobic metabolism, it is now clear that ROS generated in sub-toxic levels by different intracellular systems act as signaling molecules involved in various cellular processes including growth and cell death. Increasing evidence suggests a mutual interplay between calcium and ROS signaling systems which seems to have important implications for fine tuning cellular signaling networks. However, dysfunction in either of the systems might affect the other system thus potentiating harmful effects which might contribute to the pathogenesis of various disorders.

Stress as a modern civilization factor significantly affects our lives. While acute stress might have a positive effect on the organism, chronic stress is usually detrimental and might lead to serious health complications. It is known that stress induced by the physical environment (temperature-induced cold stress) can significantly impair the efficacy of cytotoxic chemotherapies and the anti-tumor immune response. On the other hand, epidemiological evidence has shown that patients taking drugs known as β-adrenergic antagonists (“β-blockers”), which are commonly prescribed to treat arrhythmia, hypertension, and anxiety, have significantly lower rates of several cancers. In this review, we summarize the current knowledge about catecholamines as important stress hormones in tumorigenesis and discuss the use of β-blockers as the potential therapeutic agents.

Although the involvement of type 1 (IP₃R1) and type 2 (IP₃R2) inositol 1,4,5-trisphosphate receptors in apoptosis induction has been well documented in different cancer cells and tissues, the function of type 3 IP₃R (IP₃R3) is still elusive. Therefore, in this work we focused on the role of IP₃R3 in tumor cells in vitro and in vivo. We determined increased expression of this receptor in clear cell renal cell carcinoma compared to matched unaffected part of the kidney from the same patient. Thus, we hypothesized about different functions of IP₃R3 compared to IP₃R1 and IP₃R2 in tumor cells. Silencing of IP₃R1 prevented apoptosis induction in colorectal cancer DLD1 cells, ovarian cancer A2780 cells, and clear cell renal cell carcinoma RCC4 cells, compared to apoptosis in cells treated with scrambled siRNA. As expected, silencing of IP₃R3 and subsequent apoptosis induction resulted in increased levels of apoptosis in all these cells. Further, we prepared a DLD1/IP₃R3_del cell line using CRISPR/Cas9 gene editing method. These cells were injected into nude mice and tumor's volume was compared with tumors induced by DLD1 cells. Lower volume of tumors originated from DLD1/IP₃R3_del cells was observed after 12 days, compared to wild type DLD1 cells. Also, the migration of these cells was lesser compared to wild type DLD1 cells. Apoptosis under hypoxic conditions was more pronounced in DLD1/IP₃R3_del cells than in DLD1 cells. These results clearly show that IP₃R3 has proliferative and anti-apoptotic effect in tumor cells, on contrary to the pro-apoptotic effect of IP₃R1.

The sodium/calcium exchanger (NCX) is a unique calcium transport system, generally transporting calcium ions out of the cell in exchange for sodium ions. Nevertheless, under special conditions this transporter can also work in a reverse mode, in which direction of the ion transport is inverted—calcium ions are transported inside the cell and sodium ions are transported out of the cell. To date, three isoforms of the NCX have been identified and characterized in humans. Majority of information about the NCX function comes from isoform 1 (NCX1). Although knowledge about NCX function has evolved rapidly in recent years, little is known about these transport systems in cancer cells. This review aims to summarize current knowledge about NCX functions in individual types of cancer cells.

Knowledge about the expression and thus a role of enzymes that produce endogenous H2S - cystathionine-β-synthase, cystathionine γ-lyase and mercaptopyruvate sulfurtransferase - in renal tumors is still controversial. In this study we aimed to determine the expression of these enzymes relatively to the expression in unaffected part of kidney from the same patient and to found relation of these changes to apoptosis. To evaluate patient’s samples, microarray and immunohistochemistry was used. To determine the physiological importance, we used RCC4 stable cell line derived from clear cell renal cell carcinoma, where apoptosis induction by a mixture of five chemotherapeutics with/without silencing of H2S-producing enzymes was detected. Immunofluorescence was used to determine each enzyme in the cells. In clear cell renal cell carcinomas, expression of H2S-producing enzymes was mostly decreased compared to a part of kidney that was distal from the tumor. To evaluate a potential role of H2S-producing enzymes in the apoptosis induction, we used RCC4 stable cell line. We have found that silencing of cystathionine-β-synthase and cystathionine γ-lyase prevented induction of apoptosis. Immunofluorescence staining clearly showed that these enzymes were upregulated during apoptosis in RCC4 cells. Based on these results we concluded that in clear cell renal cell carcinoma, reduced expression of the H2S-producing enzymes, mainly cystathionine γ-lyase, might contribute to a resistance to the induction of apoptosis. Increased production of the endogenous H2S, or donation from the external sources might be of a therapeutic importance in these tumors.