Calcium (Ca²⁺) is a major second messenger in cells and is essential for the fate and survival of all higher organisms. Different Ca²⁺ channels, pumps, or exchangers regulate variations in the duration and levels of intracellular Ca²⁺, which may be transient or sustained. These changes are then decoded by an elaborate toolkit of Ca²⁺-sensors, which translate Ca²⁺ signal to intracellular operational cell machinery, thereby regulating numerous Ca²⁺-dependent physiological processes. Alterations to Ca²⁺ homoeostasis and signaling are often deleterious and are associated with certain pathological states, including cancer. Altered Ca²⁺ transmission has been implicated in a variety of processes fundamental for the uncontrolled proliferation and invasiveness of tumor cells and other processes important for cancer progression, such as the development of resistance to cancer therapies. Here, we review what is known about Ca²⁺ signaling and how this fundamental second messenger regulates life and death decisions in the context of cancer, with particular attention directed to cell proliferation, apoptosis, and autophagy. We also explore the intersections of Ca²⁺ and the therapeutic targeting of cancer cells, summarizing the therapeutic opportunities for Ca²⁺ signal modulators to improve the effectiveness of current anticancer therapies.

The divalent cation calcium (Ca²⁺) is considered one of the main second messengers inside cells and acts as the most prominent signal in a plethora of biological processes. Its homeostasis is guaranteed by an intricate and complex system of channels, pumps, and exchangers. In this context, by regulating cellular Ca²⁺ levels, mitochondria control both the uptake and release of Ca²⁺. Therefore, at the mitochondrial level, Ca²⁺ plays a dual role, participating in both vital physiological processes (ATP production and regulation of mitochondrial metabolism) and pathophysiological processes (cell death, cancer progression and metastasis). Hence, it is not surprising that alterations in mitochondrial Ca²⁺ (mCa²⁺) pathways or mutations in Ca²⁺ transporters affect the activities and functions of the entire cell. Indeed, it is widely recognized that dysregulation of mCa²⁺ signaling leads to various pathological scenarios, including cancer, neurological defects and cardiovascular diseases (CVDs). This review summarizes the current knowledge on the regulation of mCa²⁺ homeostasis, the related mechanisms and the significance of this regulation in physiology and human diseases. We also highlight strategies aimed at remedying mCa²⁺ dysregulation as promising therapeutical approaches.

Mitochondria are key regulators of cell survival and are involved in a plethora of mechanisms, such as metabolism, Ca²⁺ signaling, reactive oxygen species (ROS) production, mitophagy and mitochondrial transfer, fusion, and fission (known as mitochondrial dynamics). The tuning of these processes in pathophysiological conditions is fundamental to the balance between cell death and survival. Indeed, ROS overproduction and mitochondrial Ca²⁺ overload are linked to the induction of apoptosis, while the impairment of mitochondrial dynamics and metabolism can have a double-faceted role in the decision between cell survival and death. Tumorigenesis involves an intricate series of cellular impairments not yet completely clarified, and a further level of complexity is added by the onset of apoptosis resistance mechanisms in cancer cells. In the majority of cases, cancer relapse or lack of responsiveness is related to the emergence of chemoresistance, which may be due to the cooperation of several cellular protection mechanisms, often mitochondria-related. With this review, we aim to critically report the current evidence on the relationship between mitochondria and cancer chemoresistance with a particular focus on the involvement of mitochondrial dynamics, mitochondrial Ca²⁺ signaling, oxidative stress, and metabolism to possibly identify new approaches or targets for overcoming cancer resistance.

Role of calcium in polycystic kidney disease: From signaling to pathology

Patients suffering from metastatic renal cell carcinoma (mRCC) show an overall survival rate of lower than 10% after 5 years from diagnosis. Currently, the first-line treatment for mRCC patients is based on antiangiogenic drugs that are able to inhibit tyrosine kinase receptors (TKI) in combination with immuno-oncology (IO) therapy or IO-IO treatments. Second-line therapy involves the use of other TKIs, immunotherapeutic drugs, and mTOR inhibitors. Nevertheless, many patients treated with mTOR and TK inhibitors acquire drug resistance, making the therapy ineffective. Therefore, the research of new therapeutic targets is crucial for improving the overall survival and quality of life of mRCC patients. The investigation of the molecular basis of RCC, especially in clear cell renal cell carcinoma (ccRCC), has led to the identification of different signaling pathways that are involved in renal carcinogenesis. Most of ccRCCs are associated with mutation in VHL gene, which mediates the degradation of hypoxia-inducible factors (HIFs), that, in turn, regulate the pathways related to tumorigenesis, including angiogenesis and invasion. Renal tumorigenesis is also associated with the activation of tyrosine kinases that modulate the PI3K-Akt-mTOR pathway, promoting cell proliferation and survival. In ccRCC, the abnormal activity of mTOR activates the MDM2 protein, which leads to the degradation of tumor suppressor p53 via proteasome machinery. In addition, p53 may be degraded by autophagy in a mechanism involving the enzyme transglutaminase 2 (TG2). Suppression of wild-type p53 promotes cell growth, invasion, and drug resistance. Finally, the activation of ferroptosis appears to inhibit cancer progression in RCC. In conclusion, these pathways might represent new therapeutic targets for mRCC.