Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival

Moore, Paul C.; Qi, Jenny Y.; Thamsen, Maike; Ghosh, Rajarshi; Peng, James; Gliedt, Micah J.; Meza-Acevedo, Rosa; Warren, Rachel E.; Hiniker, Annie; Kim, Grace; Maly, Dustin J.; Backes, Bradley J.; Papa, Feroz R.; Oakes, Scott A.

doi:10.1158/0008-5472.can-19-1116

Cited by 25 publications

(11 citation statements)

References 62 publications

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“…Consistent with findings that B-I09 induces apoptosis in CARM1-expressing cells, the pro-apoptotic ER stress effector CHOP expression 22 was induced by B-I09 in CARM1-expressing cells (Supplementary Fig. 4o, p ).…”

Section: Resultssupporting

confidence: 90%

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

et al. 2021

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CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

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Section: Resultssupporting

confidence: 90%

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

et al. 2021

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“…The sensors PERK, IRE1 and ATF6 are pivotal to the UPR, together with their downstream transcription factors. When activated, the consequent UPR will trigger adaptation or apoptosis depending on the level of ER stress [ 48 ]. These proteins aim to restore homeostasis, but they can also induce cell death [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

Estarás

Gonzalez

Fernandez–Bermejo

et al. 2021

IJMS

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In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM–1 µM) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2α and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of α-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.

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“…For instance, the downstream target genes of ATF6 can be compensated by XBP1 during acute silence of ATF6 [30]. Inhibition of PERK leads to the compensatory activation of XBP1s, and the inhibition of IRE1α contributes to the sustained activation of PERK and CHOP [31]. In addition, hyperactivation of IRE1α is found in the XBP1 deletion hepatocyte [32].…”

Section: Fundamental Roles Of Er Stress and Unfolded Protein Responsesmentioning

confidence: 99%

Therapeutic Approaches Targeting Proteostasis in Kidney Disease and Fibrosis

Chen

Chiang

2021

IJMS

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Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called “ER stress”. Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.

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Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival

Cited by 25 publications

References 62 publications

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

Therapeutic Approaches Targeting Proteostasis in Kidney Disease and Fibrosis

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