Relevance of Membrane Contact Sites in Cancer Progression

Abstract

Membrane contact sites (MCS) are typically defined as areas of proximity between heterologous or homologous membranes characterized by specific proteins. The study of MCS is considered as an emergent field that shows how crucial organelle interactions are in cell physiology. MCS regulate a myriad of physiological processes such as apoptosis, calcium, and lipid signaling, just to name a few. The membranal interactions between the endoplasmic reticulum (ER)–mitochondria, the ER–plasma membrane, and the vesicular traffic have received special attention in recent years, particularly in cancer research, in which it has been proposed that MCS regulate tumor metabolism and fate, contributing to their progression. However, as the therapeutic or diagnostic potential of MCS has not been fully revisited, in this review, we provide recent information on MCS relevance on calcium and lipid signaling in cancer cells and on its role in tumor progression. We also describe some proteins associated with MCS, like CERT, STIM1, VDAC, and Orai, that impact on cancer progression and that could be a possible diagnostic marker. Overall, these information might contribute to the understanding of the complex biology of cancer cells.

Surface cholesterol-enriched domains specifically promote invasion of breast cancer cell lines by controlling invadopodia and extracellular matrix degradation

“…Converging evidences in the literature indicate that, after synthesis in the ER, the transport of chol is fast and carried between membranes by lipid transfer proteins. We here showed that the ER-PM contact sites were more extended in the malignant cells, in agreement with their proposed role in cancer progression [ 47 , 48 ]. Moreover, chol depletion decreased both ER-PM contacts and chol surface exposure, consistent with the accumulation of ER-resident proteins at ER-PM contact sites upon chol supplementation [ 49 , 50 ].…”

Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance

“…MCS are specialized small areas of close apposition between two organelles and at the LE/Lys-ER interface, lipid and cholesterol transfer proteins, together with tethers, sorting nexins, membrane channels, SNAREs, small Rab-GTPases and annexins mediate ion and lipid exchange [9][10][11][12]145,146]. It would go beyond the scope of this review to list all MCS-associated proteins, and we recommend excellent reviews that address the association of MCS with cancer-related events for further reading [147][148][149][150]. Most important here, NPC1-dependent and -independent cholesterol transfer mechanisms across MCS between LE/Lys and the ER involve members of the StARD and ORP families, Rab7 and their regulators and effectors, as well as the scaffolding protein annexin AnxA6 [9][10][11][12]145,146], all of which with links to cancer that will be described in more detail in the following sections.…”

Ca2+ Transportome and the Interorganelle Communication in Hepatocellular Carcinoma

“…Indeed, mitochondria were found to be positioned at the cytosolic edge facing the ER, and in actual contact with ER Ca 2+ transporters [ 95 ]. The MCSs enable the exchange of signals involving a set of various proteins and contribute to mitochondrial Ca 2+ signalling due to the plausible uptake of ER-released Ca 2+ through the MCU, possibly via IP 3 R and MCU-associated proteins [ 98 , 99 ].…”