An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer

Robinson, Claire M.; Talty, Aaron; Logue, Susan E.; Mnich, Katarzyna; Gorman, Adrienne M.; Samali, Afshin

doi:10.3390/cancers13020261

Cited by 31 publications

(29 citation statements)

References 118 publications

(89 reference statements)

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“…A number of circumstances favor the onset of an ER stress response in cancer cells, including a rapid cell proliferation leading to a protein build-up, inhibition of protein glycosylation, imbalance of ER calcium levels, as well as localized depletion of oxygen, nutrients, and glucose in the tumor microenvironment, which could be related to cancer chemoresistance [107]. This ER stress condition, characterized by the accumulation of misfolded proteins inside the ER lumen, triggers the unfolded protein response (UPR) [106,107], which is controlled by three ER transmembrane stress sensors-namely, inositol-requiring enzyme 1 (IRE1) [108], protein kinase RNA (PKR)-like ER kinase (PERK) [109], and activating transcription factor 6 (ATF6) [110]-with the main aim being to restore the ER's physiological activity. This UPR signal transduction is fundamentally a pro-survival process, although sustained or protracted ER stress may result in cell death [106].…”

Section: Er Stress and Cancer Resistancementioning

confidence: 99%

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Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Mollinedo

Gajate

2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

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Section: Er Stress and Cancer Resistancementioning

confidence: 99%

“…Sustained ER stress is induced in chronic pancreatitis [112], and pancreatic tumors tend to show high basal levels of ER stress [107]. Furthermore, autophagy seems to play an essential role in PDAC survival and progression, likely providing fuel to pancreatic cancer cells in their nutrient-deprived environment [113].…”

Section: Er Stress and Cancer Resistancementioning

confidence: 99%

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Mollinedo

Gajate

2021

Cancers

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“…Tumor microenvironment and cell signaling cascade play a key role in pancreatic cancer, while UPR is responsible for maintaining cell homeostasis and regulating a variety of signaling pathways that affect cell behavior. Therefore, UPR in pancreatic cancer cells is a potential target to overcome drug resistance of pancreatic cancer [16].…”

Section: Er Stress and Uprmentioning

confidence: 99%

Unfolded protein response activated by endoplasmic reticulum stress in pancreatic cancer: potential therapeutical target

Long¹,

Chen²,

Yang³

et al. 2021

Front. Biosci. (Landmark Ed)

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“…These changes induce the unfolded protein response (UPR), essentially by three ER-related transmembrane proteins i.e. the inositol-requiring enzyme 1, the protein kinase RNAlike endoplasmic reticulum kinase, and the activating transcription factor 6 [70][71][72][73]. CCL2 and other chemokines, together with oxidative stress, trigger ER stress.…”

Section: Mechanism Of Action Of Ccl2 In the Immune Response And Inflammation And Its Relationship With Multiple Metabolic Alterationsmentioning

confidence: 99%

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

Camps¹,

Castañé²,

Rodríguez-Tomàs³

et al. 2021

Preprint

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Infectious as well as most non-infectious diseases share certain common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors, produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, they produce metabolic alterations that influence the pathogenesis of the disease. In this review we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, which induces migration and infiltration of immune cells in target tissues, and is involved in disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets.

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An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer

Cited by 31 publications

References 118 publications

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Unfolded protein response activated by endoplasmic reticulum stress in pancreatic cancer: potential therapeutical target

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

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