Calcium Permeable Channels in Cancer Hallmarks

Abstract

Cancer, the second cause of death worldwide, is characterized by several common criteria, known as the "cancer hallmarks" such as unrestrained cell proliferation, cell death resistance, angiogenesis, invasion and metastasis. Calcium permeable channels are proteins present in external and internal biological membranes, diffusing Ca 2+ ions down their electrochemical gradient. Numerous physiological functions are mediated by calcium channels, ranging from intracellular calcium homeostasis to sensory transduction. Consequently, calcium channels play important roles in human physiology and it is not a surprise the increasing number of evidences connecting calcium channels disorders with tumor cells growth, survival and migration. Multiple studies suggest that calcium signals are augmented in various cancer cell types, contributing to cancer hallmarks. This review focuses in the role of calcium permeable channels signaling in cancer with special attention to the mechanisms behind the remodeling of the calcium signals. Transient Receptor Potential (TRP) channels and Store Operated Channels (SOC) are the main extracellular Ca 2+ source in the plasma membrane of nonexcitable cells, while inositol trisphosphate receptors (IP 3 R) are the main channels releasing Ca 2+ from the endoplasmic reticulum (ER). Alterations in the function and/or expression of these calcium channels, as wells as, the calcium buffering by mitochondria affect intracellular calcium homeostasis and signaling, contributing to the transformation of normal cells into their tumor counterparts. Several compounds reported to counteract several cancer hallmarks also modulate the activity and/or the expression of these channels including non-steroidal anti-inflammatory drugs (NSAIDs) like sulindac and aspirin, and inhibitors of polyamine biosynthesis, like difluoromethylornithine (DFMO). The possible role of the calcium permeable channels targeted by these compounds in cancer and their action mechanism will be discussed also in the review.

Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma

“…Several reports have identified Ca 2+ channels as essential in different cancer stem cells, although the specific roles of SOC remain to be clarified [ 65 , 66 ]. This central role of Ca 2+ is not restricted to stem cells but also relates to overall tumor progression, which has led to suggestions that Ca 2+ dyshomeostasis is a hallmark of cancer [ 67 , 68 ]. Thus, it would be of interest to design future studies to determine the extent to which Ca 2+ dyshomeostasis [ 10 , 14 ] affects GSC activities and to fully explore the Ca 2+ toolkit involved in GBM initiation, progression and recurrence.…”

A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies

“…Also very relevant are the community effects associated with cell electrical communication, leading to both short and long range influence and patterns 42 , and their importance in cancer, as the link between the cells’ bioelectric state and invasiveness 49 or the role signaling by calcium permeable channels play in tumor progress 50 . The manipulation of the tissue bioelectric state, profiting from the long range impact and propagation of the polarization state, can be an effective and efficient approach for cancer prevention and therapy.…”

Molecular Choreography and Structure of Ca2+ Release-Activated Ca2+ (CRAC) and KCa2+ Channels and Their Relevance in Disease with Special Focus on Cancer

“…Defects in the cellular Ca 2+ homeostasis due to dysfunction or changes in the occurrence of one of these molecular key players in Ca 2+ signal transduction can be responsible for severe immune deficiencies, neuronal diseases or heart problems. Moreover, altered Ca 2+ signaling can lead to various cancers by regulating one or more of the known cancer hallmarks [ 19 , 32 , 33 ] such as sustained proliferation signals, apoptosis resistance, evading growth suppressors, induction of angiogenesis, replicative immortality, tissue invasion, and metastasis cancer hallmarks [ 6 , 7 , 8 , 32 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”