scholarly journals ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Danilo Swann Matassa ◽  
Diana Arzeni ◽  
Matteo Landriscina ◽  
Franca Esposito
Keyword(s):  
Protein Synthesis ◽  
Cancer Cells ◽  
Protein Quality ◽  
Mitochondrial Permeability Transition ◽  
Metabolic Stress ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Regulatory Mechanisms ◽  
Great Promise ◽  
Integrated Network

AbstractTRAP1 is an HSP90 chaperone, upregulated in human cancers and involved in organelles’ homeostasis and tumor cell metabolism. Indeed, TRAP1 is a key regulator of adaptive responses used by highly proliferative tumors to face the metabolic stress induced by increased demand of protein synthesis and hostile environments. Besides well-characterized roles in prevention of mitochondrial permeability transition pore opening and in regulating mitochondrial respiration, TRAP1 is involved in novel regulatory mechanisms: i) the attenuation of global protein synthesis, ii) the co-translational regulation of protein synthesis and ubiquitination of specific client proteins, and iii) the protection from Endoplasmic Reticulum stress. This provides a crucial role to TRAP1 in maintaining cellular homeostasis through protein quality control, by avoiding the accumulation of damaged or misfolded proteins and, likely, facilitating the synthesis of selective cancer-related proteins. Herein, we summarize how these regulatory mechanisms are part of an integrated network, which enables cancer cells to modulate their metabolism and to face, at the same time, oxidative and metabolic stress, oxygen and nutrient deprivation, increased demand of energy production and macromolecule biosynthesis. The possibility to undertake a new strategy to disrupt such networks of integrated control in cancer cells holds great promise for treatment of human malignancies.

Mitochondrial calcium exchange in physiology and disease

2021 ◽  
Author(s):  
Joanne F Garbincius ◽  
John W. Elrod
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Neuromuscular Disorders ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Genetic Identification ◽  
Calcium Flux ◽  
Great Promise ◽  
Mitochondrial Calcium ◽  
Inner Mitochondrial Membrane ◽  
Fundamental Biological Process

The uptake of calcium into and extrusion of calcium from the mitochondrial matrix is a fundamental biological process that has critical effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium (mCa2+) cycling is implicated in numerous acquired diseases such as heart failure, stroke, neurodegeneration, diabetes, and cancer, and is genetically linked to several inherited neuromuscular disorders. Understanding the mechanisms responsible for mCa2+ exchange therefore holds great promise for the treatment of these diseases. The past decade has seen the genetic identification of many of the key proteins that mediate mitochondrial calcium uptake and efflux. Here, we present an overview of the phenomenon of mCa2+ transport, and a comprehensive examination of the molecular machinery that mediates calcium flux across the inner mitochondrial membrane: the mitochondrial uniporter complex (consisting of MCU, EMRE, MICU1, MICU2, MICU3, MCUB, and MCUR1), NCLX, LETM1, the mitochondrial ryanodine receptor, and the mitochondrial permeability transition pore. We then consider the physiological implications of mCa2+ flux and evaluate how alterations in mCa2+ homeostasis contribute to human disease. This review concludes by highlighting opportunities and challenges for therapeutic intervention in pathologies characterized by aberrant mCa2+ handling and by summarizing critical unanswered questions regarding the biology of mCa2+ flux.

scholarly journals Mipsagargin: The Beginning—Not the End—of Thapsigargin Prodrug-Based Cancer Therapeutics

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7469
Author(s):  
John T. Isaacs ◽  
William Nathaniel Brennen ◽  
Søren Brøgger Christensen ◽  
Samuel R. Denmeade
Keyword(s):  
Cancer Cells ◽  
Water Solubility ◽  
Mitochondrial Permeability Transition ◽  
Specific Antigen ◽  
Cancer Therapeutics ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Therapeutic Index ◽  
Water Soluble ◽  
Systemic Delivery

Søren Brøgger Christensen isolated and characterized the cell-penetrant sesquiterpene lactone Thapsigargin (TG) from the fruit Thapsia garganica. In the late 1980s/early 1990s, TG was supplied to multiple independent and collaborative groups. Using this TG, studies documented with a large variety of mammalian cell types that TG rapidly (i.e., within seconds to a minute) penetrates cells, resulting in an essentially irreversible binding and inhibiting (IC50~10 nM) of SERCA 2b calcium uptake pumps. If exposure to 50–100 nM TG is sustained for >24–48 h, prostate cancer cells undergo apoptotic death. TG-induced death requires changes in the cytoplasmic Ca2+, initiating a calmodulin/calcineurin/calpain-dependent signaling cascade that involves BAD-dependent opening of the mitochondrial permeability transition pore (MPTP); this releases cytochrome C into the cytoplasm, activating caspases and nucleases. Chemically unmodified TG has no therapeutic index and is poorly water soluble. A TG analog, in which the 8-acyl groups is replaced with the 12-aminododecanoyl group, afforded 12-ADT, retaining an EC50 for killing of <100 nM. Conjugation of 12-ADT to a series of 5–8 amino acid peptides was engineered so that they are efficiently hydrolyzed by only one of a series of proteases [e.g., KLK3 (also known as Prostate Specific Antigen); KLK2 (also known as hK2); Fibroblast Activation Protein Protease (FAP); or Folh1 (also known as Prostate Specific Membrane Antigen)]. The obtained conjugates have increased water solubility for systemic delivery in the blood and prevent cell penetrance and, thus, killing until the TG-prodrug is hydrolyzed by the targeting protease in the vicinity of the cancer cells. We summarize the preclinical validation of each of these TG-prodrugs with special attention to the PSMA TG-prodrug, Mipsagargin, which is in phase II clinical testing.

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