Abstract
In recent decades, compelling evidence has emerged showing that organelles are not static structures but rather form a highly dynamic cellular network and exchange information through membrane contact sites. Although high-throughput techniques facilitate identification of novel contact sites (e.g., organelle-organelle and organelle-vesicle interactions), little is known about their impact on cellular physiology. Moreover, even less is known about how the dysregulation of these structures impacts on cellular function and therefore, disease. Particularly, cancer cells display altered signaling pathways involving several cell organelles; however, the relevance of interorganelle communication in oncogenesis and/or cancer progression remains largely unknown. This review will focus on organelle contacts relevant to cancer pathogenesis. We will highlight specific proteins and protein families residing in these organelle-interfaces that are known to be involved in cancer-related processes. First, we will review the relevance of endoplasmic reticulum (ER)-mitochondria interactions. This section will focus on mitochondria-associated membranes (MAMs) and particularly the tethering proteins at the ER-mitochondria interphase, as well as their role in cancer disease progression. Subsequently, the role of Ca2+ at the ER-mitochondria interphase in cancer disease progression will be discussed. Members of the Bcl-2 protein family, key regulators of cell death, also modulate Ca2+ transport pathways at the ER-mitochondria interphase. Furthermore, we will review the role of ER-mitochondria communication in the regulation of proteostasis, focusing on the ER stress sensor PERK (PRKR-like ER kinase), which exerts dual roles in cancer. Second, we will review the relevance of ER and mitochondria interactions with other organelles. This section will focus on peroxisome and lysosome organelle interactions and their impact on cancer disease progression. In this context, the peroxisome biogenesis factor (PEX) gene family has been linked to cancer. Moreover, the autophagy-lysosome system is emerging as a driving force in the progression of numerous human cancers. Thus, we will summarize our current understanding of the role of each of these organelles and their communication, highlighting how alterations in organelle interfaces participate in cancer development and progression. A better understanding of specific organelle communication sites and their relevant proteins may help to identify potential pharmacological targets for novel therapies in cancer control.
Highlights
Higher organisms are characterized by the cooperation between cell populations, which carry out different, complementary functions
Cancer cells proliferate uncontrollably, and they avoid differentiation and attain several special traits, such as the ability to increase the supply of nutrients, become invisible to the immune system, change their metabolism and adapt to surroundings that vary as the tumor progresses, among others (Fouad and Aanei, 2017)
Caveolin-1 (CAV1), a membrane-associated scaffolding protein, that acts both as a tumor suppressor and a promoter of metastasis depending on the type of cancer and stage (Campos et al, 2019; Simon et al, 2020), is enriched in mitochondria-associated ER membranes (MAMs) (Sala-Vila et al, 2016; Bravo-Sagua et al, 2019; Figure 1)
Summary
Higher organisms are characterized by the cooperation between cell populations, which carry out different, complementary functions. There CAV1 plays a controversial role; on the one hand, CAV1 reportedly limits the adaptation to stress in tumor cells through impairment of ER-mitochondria contacts (Bravo-Sagua et al, 2019); on the other hand, using livers from wild-type and CAV1-deficient mice, it was shown that CAV1 promotes ER-mitochondria contacts, thereby contributing to the recruitment and regulation of intracellular steroids and lipoprotein metabolism (Sala-Vila et al, 2016). Proteins encoded by oncogenes and tumor suppressors modulate ER IP3R activity in MAMs, altering Ca2+ signaling in cancer cells (Fan et al, 2017). The dysregulation of proteins involved in Ca2+ transport at MAMs or in oncogenes and tumor suppressor proteins in cancer, alters Ca2+ transfer from the ER to the mitochondria, and, whether the outcome is the inhibition of Ca2+ transfer or Ca2+ overload, it will contribute directly to cancer disease progression by modulating cell death and/or survival. While PERK contributes to tighter MAMs during ER stress-induced apoptosis (Verfaillie et al, 2012), other roles of MAM resident-PERK and their contribution to cancer disease progression remain unclear
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