Perspectives on Organelle Interaction, Protein Dysregulation, and Cancer Disease

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.

Genetic variants in DDO and PEX5L in peroxisome‐related pathways predict non‐small cell lung cancer survival

“…The role of peroxisomes in lung cancer is not well understood, and more mechanistic studies may reveal treatment targets in peroxisome-related pathways. 63 The present study demonstrates associations between two SNPs in two genes involved in peroxisome functions and survival of NSCLC. However, the present study has several limitations, including being conducted using a sample of only Caucasian patients, which may reduce generalizability to all populations.…”

“…The role of peroxisomes in lung cancer is not well understood, and more mechanistic studies may reveal treatment targets in peroxisome‐related pathways 63 . The present study demonstrates associations between two SNPs in two genes involved in peroxisome functions and survival of NSCLC.…”

Characterization of the AGR2 Interactome Uncovers New Players of Protein Disulfide Isomerase Network in Cancer Cells

“…This facilitates Ca 2+ ion exchange and maintains Ca 2+ homeostasis. Stress-70 protein (mitochondrial), also known as 75 kDa glucose-regulated chaperone GRP75/HSPA9, plays active role in intermembrane complex formation and through this in intracellular signal transduction (61).…”

NLRP3-Mediated Inflammation in Atherosclerosis and Associated Therapeutics

“…PERK, a transmembrane protein kinase, connects NLRP3 inflammasome through mitochondria-associated membranes (MAMs) ( Han et al, 2018 ), and engages in NLRP3 inflammasome activation ( Lebeaupin et al, 2015 ). PERK deficiency results in mitochondrial fragmentation and shorted ER–mitochondria communication that decrease ROS production depending on the level of ER stress and the activity of NLRP3 inflammasome ( Diaz et al, 2021 ). Meanwhile, PERK inhibitor disrupts ER-derived Ca 2+ release due to MAMs perturbation, thus blocking activation of the inflammasome ( Zhou et al, 2020 ).…”