The ER-mitochondria Ca2+ signaling in cancer progression: Fueling the monster

Abstract

Cancer is a leading cause of death worldwide. All major tumor suppressors and oncogenes are now recognized to have fundamental connections with metabolic pathways. A hallmark feature of cancer cells is a reprogramming of their metabolism even when nutrients are available. Increasing evidence indicates that most cancer cells rely on mitochondrial metabolism to sustain their energetic and biosynthetic demands. Mitochondria are functionally and physically coupled to the endoplasmic reticulum (ER), the major calcium (Ca²⁺) storage organelle in mammalian cells, through special domains known as mitochondria-ER contact sites (MERCS). In this domain, the release of Ca²⁺ from the ER is mainly regulated by inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), a family of Ca²⁺ release channels activated by the ligand IP3. IP3R mediated Ca²⁺ release is transferred to mitochondria through the mitochondrial Ca²⁺ uniporter (MCU). Once in the mitochondrial matrix, Ca²⁺ activates several proteins that stimulate mitochondrial performance. The role of IP3R and MCU in cancer, as well as the other proteins that enable the Ca²⁺ communication between these two organelles is just beginning to be understood. Here, we describe the function of the main players of the ER mitochondrial Ca²⁺ communication and discuss how this particular signal may contribute to the rise and development of cancer traits.

Keywords: Cancer hallmarks; IP3R; MCUC; Metabolism; Mitochondria-associated membranes (MAMs).