Crosstalk between calcium and reactive oxygen species signaling in cancer revisited

The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca²⁺) are intricately linked. ROS signaling and Ca²⁺ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca²⁺ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca²⁺ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca²⁺ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca²⁺ signals. At one end of the spectrum, Ca²⁺ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca²⁺ and ROS in cancer progression, emphasize the impact of redox regulation on Ca²⁺ transport mechanisms, and describe how Ca²⁺ signaling pathways, in turn, can regulate the cellular redox environment.